Cyclooxygenase-2 selective inhibitors, compositions and methods of use

ABSTRACT

The invention describes novel cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No.60/398,829 filed Jul. 29, 2002.

FIELD OF THE INVENTION

[0002] The invention describes novel nitrosated and/or nitrosylatedcyclooxygenase 2 (COX-2) selective inhibitors and novel compositionscomprising at least one nitrosated and/or nitrosylated cyclooxygenase 2(COX-2) selective inhibitor, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, stimulates endogenoussynthesis of nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase, and/or at least one therapeutic agent. The invention alsoprovides novel compositions comprising at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide,elevates endogenous levels of endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase and/or at least one therapeutic agent. Theinvention also provides novel kits comprising at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, optionally, at least one nitric oxide donor and/or at least onetherapeutic agent. The invention also provides methods for treatinginflammation, pain and fever; for treating gastrointestinal disordersand/or improving the gastrointestinal properties of COX-2 selectiveinhibitors; for facilitating wound healing; for treating and/orpreventing renal and/or respiratory toxicities; for treating and/orpreventing other disorders resulting from elevated levels ofcyclooxygenase-2; and for improving the cardiovascular profile of COX-2selective inhibitors.

BACKGROUND OF THE INVENTION

[0003] Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely usedfor the treatment of pain, inflammation, and acute and chronicinflammatory disorders such as osteoarthritis and rheumatoid arthritis.These compounds inhibit the activity of the enzyme cyclooxygenase (COX),also known as prostaglandin G/H synthase, which is the enzyme thatconverts arachidonic acid into prostanoids. The NSAIDs also inhibit theproduction of other prostaglandins, especially prostaglandin G₂,prostaglandin H₂ and prostaglandin E₂, thereby reducing theprostaglandin-induced pain and swelling associated with the inflammationprocess. The chronic use of NSAIDs has been associated with adverseeffects, such as gastrointestinal ulceration and renal toxicity. Theundesirable side effects are also due to the inhibition of prostaglandinin the affected organ.

[0004] Recently two isoforms of cyclooxygenase, encoded by two distinctgenes (Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective. Recently compounds that are COX-2 selective inhibitors havebeen developed and marketed. These COX-2 selective inhibitors have thedesired therapeutic profile of an antiinflammatory drug without theadverse effects commonly associated with the inhibition of COX-1.However, these compounds can result in dyspepsia and can causegastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).Additionally the COX-2 selective inhibitors can increase the risk ofcardiovascular events in a patient (Mukherjee et al., JAMA 286(8)954-959 (2001)); Hennan et al., Circulation, 104:820-825 (2001)).

[0005] There is still a need in the art for novel COX-2 selectiveinhibitor compounds that have gastroprotective properties, facilitatewound healing, decreased renal toxicity and dyspepsia, improvedcardiovascular profile and that can be used at low dosages. Theinvention is directed to these, as well as other, important ends.

SUMMARY OF THE INVENTION

[0006] The invention provides novel COX-2 selective inhibitors, or apharmaceutically acceptable salt thereof. These compounds are potentanalgesics, have antiinflammatory properties and have an unexpectedpotential for facilitating wound healing. The novel compounds also haveunexpected properties in the treatment and/or prevention of renal and/orrespiratory toxicity and for improving the cardiovascular profile ofCOX-2 selective inhibitors. The COX-2 selective inhibitor, or apharmaceutically acceptable salt thereof, can be nitrosated and/ornitrosylated through one or more sites, such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Theinvention also provides compositions comprising the novel compoundsdescribed herein in a pharmaceutically acceptable carrier.

[0007] The invention is also based on the discovery that administeringat least one COX-2 selective inhibitor and at least one nitric oxidedonor or administering at least one nitrosated and/or nitrosylated COX-2selective inhibitor, and, optionally, at least one nitric oxide donorreduces the gastrointestinal toxicity induced by COX-2 selectiveinhibitors. Nitric oxide donors include, for example, S-nitrosothiols,nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM 5185, SPM 5186and analogues thereof, and substrates of the various isozymes of nitricoxide synthase. Thus, another aspect of the invention providescompositions comprising at least one COX-2 selective inhibitor, that isoptionally substituted with at least one NO and/or NO₂ group (i.e.,nitrosylated and/or nitrosated), and at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO.), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase. Theinvention also provides for such compositions in a pharmaceuticallyacceptable carrier.

[0008] Yet another aspect of the invention provides compositionscomprising at least one COX-2 selective inhibitor, that is optionallysubstituted with at least one NO₂ group and/or at least one NO group(i.e., nitrosated and/or nitrosylated respectively), and, optionally, atleast one compound that donates, transfers or releases nitric oxide as acharged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as theneutral species, nitric oxide (NO.), and/or stimulates endogenousproduction of nitric oxide or EDRF in vivo and/or is a substrate fornitric oxide synthase, and/or, optionally, at least one therapeuticagent, including but not limited to, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. The inventionalso provides for such compositions in a pharmaceutically acceptablecarrier.

[0009] Yet another aspect of the present invention provides methods fortreating and/or preventing inflammation, pain and fever; for treatinggastrointestinal disorders and/or improving gastrointestinal propertiesof COX-2 inhibitors; for facilitating wound healing; for treating and/orpreventing renal and/or respiratory toxicity; and for treating and/orpreventing COX-2 mediated disorders (i.e., disorders resulting fromelevated levels of COX-2) in a patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally substituted withat least one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase (i.e., NO donors). The methods can optionally further comprisethe administration of at least one therapeutic agent, such as, forexample, steroids, nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,HMG CoA inhibitors, H₂ antagonists, antineoplastic agents, antiplateletagents, thrombin inhibitors, thromboxane inhibitors, decongestants,diuretics, sedating or non-sedating anti-histamines, inducible nitricoxide synthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and mixturesof two or more thereof. In this aspect of the invention, the methods caninvolve administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, administering the COX-2selective inhibitors, that are optionally nitrosated and/or nitrosylatedand NO donors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and therapeutic agents, oradministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosylated, NO donors and therapeutic agents. Theselective COX-2 inhibitors, nitric oxide donors, and/or therapeuticagents can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

[0010] Yet another aspect of the invention provides methods forimproving the cardiovascular profile of COX-2 selective inhibitors in apatient in need thereof which comprises administering to the patient atherapeutically effective amount of at least one COX-2 selectiveinhibitor, optionally substituted with at least one NO₂ and/or NO group(i.e. nitrosated and/or nitrosylated), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase (i.e. NO donor). The methods can optionally further comprisethe administration of at least one of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, and mixtures of two or more thereof.In this aspect of the invention, the methods can involve administeringthe nitrosated and/or nitrosylated COX-2 selective inhibitors,administering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosylated, and NO donors, administering the COX-2selective inhibitors, that are optionally nitrosated and/ornitrosylated, and at least one of 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors orthromboxane inhibitors, or administering the COX-2 selective inhibitors,that are optionally nitrosated and/or nitrosylated, NO donors, and atleast one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors,antiplatelet agents, thrombin inhibitors or thromboxane inhibitors. TheCOX-2 inhibitors, nitric oxide donors, and/or 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombininhibitors or thromboxane inhibitors can be administered separately oras components of the same composition in one or more pharmaceuticallyacceptable carriers.

[0011] In yet another aspect the invention provides kits comprising atleast one COX-2 selective inhibitor, that is optionally substituted withat least one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase. The kit can further comprise at least one therapeutic agent,such as, for example, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. The COX-2 selective inhibitor, the nitric oxide donor and/ortherapeutic agent, can be separate components in the kit or can be inthe form of a composition in the kit in one or more pharmaceuticallyacceptable carriers.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As used throughout the disclosure, the following terms, unlessotherwise indicated, shall be understood to have the following meanings.

[0013] “NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal antiinflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

[0014] “Cyclooxygenase-2 (COX-2) selective inhibitor” refers to acompound that selectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. In one embodiment, the compound has acyclooxygenase-2 IC₅₀ of less than about 2 μM and a cyclooxygenase-1IC₅₀ of greater than about 5 μM, in the human whole blood COX-2 assay(as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) andalso has a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 10, and preferably of at least40. In another embodiment, the compound has a cyclooxygenase-1 IC₅₀ ofgreater than about 1 μM, and preferably of greater than 20 μM. Thecompound can also inhibit the enzyme, lipoxygenase. Such selectivity mayindicate an ability to reduce the incidence of common NSAID-induced sideeffects.

[0015] “Parent COX-2 inhibitor” refers to a non-nitrosated and/ornon-nitrosylated COX-2 inhibitor, or pharmaceutically acceptable saltsthereof or pharmaceutically acceptable esters thereof. “Parent COX-2inhibitor” includes the compounds of Formulas (I), (II) and (III) beforethey are nitrosated and/or nitrosylated by the methods described herein.

[0016] “Therapeutic agent” includes any therapeutic agent that can beused to treat or prevent the diseases described herein. “Therapeuticagents” include, for example, steroids, nonsteroidal antiinflammatorycompounds, 5-lipoxygenase inhibitors, leukotriene B₄ receptorantagonists, leukotriene A₄ hydrolase inhibitors,3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. Therapeutic agentincludes the pro-drugs and pharmaceutical derivatives thereof includingbut not limited to the corresponding nitrosated and/or nitrosylatedderivatives. Although nitric oxide donors have therapeutic activity, theterm “therapeutic agent” does not include the nitric oxide donorsdescribed herein, since nitric oxide donors are separately defined.

[0017] “Cardiovascular disease or disorder” refers to any cardiovasculardisease or disorder known in the art, including, but not limited to,restenosis, atherosclerosis, atherogenesis, angina, (particularlychronic, stable angina pectoris), ischemic disease, congestive heartfailure or pulmonary edema associated with acute myocardial infarction,thrombosis, controlling blood pressure in hypertension (especiallyhypertension associated with cardiovascular surgical procedures),thromboembolic events, platelet aggregation, platelet adhesion, smoothmuscle cell proliferation, vascular complications associated with theuse of medical devices, wounds associated with the use of medicaldevices, cerebrovascular ischemic events, and the like. Complicationsassociated with the use of medical devices may occur as a result ofincreased platelet deposition, activation, thrombus formation orconsumption of platelets and coagulation proteins. Such complications,which are within the definition of “cardiovascular disease or disorder,”include, for example, myocardial infarction, ischemic stroke, transientischemic stroke, thromboembolic events, pulmonary thromboembolism,cerebral thromboembolism, thrombophlebitis, thrombocytopenia, bleedingdisorders and/or any other complications which occur either directly orindirectly as a result of the foregoing disorders.

[0018] “Restenosis” is a cardiovascular disease or disorder that refersto the closure of a peripheral or coronary artery following trauma tothe artery caused by an injury such as, for example, angioplasty,balloon dilation, atherectomy, laser ablation treatment or stentinsertion. Restenosis can also occur following a number of invasivesurgical techniques, such as, for example, transplant surgery, veingrafting, coronary artery bypass surgery, endarterectomy, hearttransplantation, balloon angioplasty, atherectomy, laser ablation,endovascular stenting, and the like.

[0019] “Atheroslcerosis” is form of chronic vascular injury in whichsome of the normal vascular smooth muscle cells in the artery wall,which ordinarily control vascular tone regulating blood flow, changetheir nature and develop “cancer-like” behavior. These vascular smoothmuscle cells become abnormally proliferative, secreting substances suchas growth factors, tissue-degradation enzymes and other proteins, whichenable them to invade and spread into the inner vessel lining, blockingblood flow and making that vessel abnormally susceptible to beingcompletely blocked by local blood clotting, resulting in the death ofthe tissue served by that artery. Atherosclerotic cardiovasculardisease, coronary heart disease (also known as coronary artery diseaseor ischemic heart disease), cerebrovascular disease and peripheralvessel disease are all common manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

[0020] “Improving the cardiovascular profile” refers to and includesreducing the risk of thromboembolic events, reducing the risk ofdeveloping atherosclerosis and atherosclerotic diseases, and inhibitingplatelet aggregation of the parent COX-2 inhibitor.

[0021] “Thromboembolic events” includes, but is not limited to, ischemicstroke, transient ischemic stroke, myocardial infarction, anginapectoris, thrombosis, thromboembolism, thrombotic occlusion andreocclusion, acute vascular events, restenosis, transient ischemicattacks, and first and subsequent thrombotic stroke. Patients who are atrisk of developing thromboembolic events, may include those with afamilial history of, or genetically predisposed to, thromboembolicdisorders, who have had ischemic stroke, transient ischemic stroke,myocardial infarction, and those with unstable angina pectoris orchronic stable angina pectoris and patients with alteredprostacyclin/thromboxane A₂ homeostasis or higher than normalthromboxane A₂ levels leading to increase risk for thromboembolism,including patients with diabetes and rheumatoid arthritis.

[0022] “Thromboxane inhibitor” refers to any compound that reversibly orirreversibly inhibits thromboxane synthesis, and includes compoundswhich are the so-called thromboxane A₂ receptor antagonists, thromboxaneA₂ antagonists, thromboxane A₂/prostaglandin endoperoxide antagonists,thromboxane receptor (TP) antagonists, thromboxane antagonists,thromboxane synthase inhibitors, and dual acting thromboxane synthaseinhibitors and thromboxane receptor antagonists. The characteristics ofthe preferred thromboxane inhibitor should include the suppression ofthromboxane A₂ formation (thromboxane synthase inhibitors) and/orblockade of thromboxane A₂ and prostaglandin H₂ platelet and vessel wall(thromboxane receptor antagonists). The effects should block plateletactivation and therefore platelet function.

[0023] “Thromboxane A₂ receptor antagonist” refers to any compound thatreversibly or irreversibly blocks the activation of any thromboxane A₂receptor.

[0024] “Thromboxane synthase inhibitor” refers to any compound thatreversibly or irreversibly inhibits the enzyme thromboxane synthesisthereby reducing the formation of thromboxane A₂. Thromboxane synthaseinhibitors may also increase the synthesis of antiaggregatoryprostaglandins including prostacyclin and prostaglandin D₂. ThromboxaneA₂ receptor antagonists and thromboxane synthase inhibitors and can beidentified using the assays described in Tai, Methods of Enzymology,Vol. 86, 110-113 (1982); Hall, Medicinal Research Reviews, 11:503-579(1991) and Coleman et al., Pharmacol Rev., 46: 205-229 (1994) andreferences therein, the disclosures of which are incorporated herein byreference in its entirety.

[0025] “Dual acting thromboxane receptor antagonist and thromboxanesynthase inhibitor” refers to any compound that simultaneously acts as athromboxane A₂ receptor antagonist and a thromboxane synthase inhibitor.

[0026] “Thrombin inhibitors” refers to and includes compounds thatinhibit hydrolytic activity of thrombin, including the catalyticconversion of fibrinogen to fibrin, activation of Factor V to Va, FactorVIII to VIIIa, Factor XIII to XIIIa and platelet activation. Thrombininhibitors may be identified using assays described in Lewis et at.,Thrombosis Research. 70: 173-190 (1993).

[0027] “Platelet aggregation” refers to the binding of one or moreplatelets to each other. Platelet aggregation is commonly referred to inthe context of generalized atherosclerosis, not with respect to plateletadhesion on vasculature damaged as a result of physical injury during amedical procedure. Platelet aggregation requires platelet activationwhich depends on the interaction between the ligand and its specificplatelet surface receptor.

[0028] “Platelet activation” refers either to the change in conformation(shape) of a cell, expression of cell surface proteins (e.g., theIIb/IIIa receptor complex, loss of GPIb surface protein), and secretionof platelet derived factors (e.g., serotonin, growth factors).

[0029] “Patient” refers to animals, preferably mammals, most preferablyhumans, and includes males and females, and children and adults.

[0030] “Therapeutically effective amount” refers to the amount of thecompound and/or composition that is effective to achieve its intendedpurpose.

[0031] “Transdermal” refers to the delivery of a compound by passagethrough the skin and into the blood stream.

[0032] “Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

[0033] “Penetration enhancement” or “permeation enhancement” refers toan increase in the permeability of the skin or mucosal tissue to aselected pharmacologically active compound such that the rate at whichthe compound permeates through the skin or mucosal tissue is increased.

[0034] “Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

[0035] “Nitric oxide adduct” or “NO adduct” refers to compounds andfunctional groups which, under physiological conditions, can donate,release and/or directly or indirectly transfer any of the three redoxforms of nitrogen monoxide (NO+, NO−, NO.), such that the biologicalactivity of the nitrogen monoxide species is expressed at the intendedsite of action.

[0036] “Nitric oxide releasing” or “nitric oxide donating” refers tomethods of donating, releasing and/or directly or indirectlytransferring any of the three redox forms of nitrogen monoxide (NO⁺,NO−, NO.), such that the biological activity of the nitrogen monoxidespecies is expressed at the intended site of action.

[0037] “Nitric oxide donor” or “NO donor” refers to compounds thatdonate, release and/or directly or indirectly transfer a nitrogenmonoxide species, and/or stimulate the endogenous production of nitricoxide or endothelium-derived relaxing factor (EDRF) in vivo and/orelevate endogenous levels of nitric oxide or EDRF in vivo. “NO donor”also includes compounds that are substrates for nitric oxide synthase.

[0038] “Alkyl” refers to a lower alkyl group, a haloalkyl group, ahydroxyalkyl group, an alkenyl group, an alkynyl group, a bridgedcycloalkyl group, a cycloalkyl group or a heterocyclic ring, as definedherein. An alkyl group may also comprise one or more radical species,such as, for example a cycloalkylalkyl group or a heterocyclicalkylgroup.

[0039] “Lower alkyl” refers to branched or straight chain acyclic alkylgroup comprising one to about ten carbon atoms (preferably one to abouteight carbon atoms, more preferably one to about six carbon atoms).Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl,hexyl, octyl, and the like.

[0040] “Substituted lower alkyl” refers to a lower alkyl group, asdefined herein, wherein one or more of the hydrogen atoms have beenreplaced with one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ isindependently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, acyano or an amino group, as defined herein.

[0041] “Haloalkyl” refers to a lower alkyl group, an alkenyl group, analkynyl group, a bridged cycloalkyl group, a cycloalkyl group or aheterocyclic ring, as defined herein, to which is appended one or morehalogens, as defined herein. Exemplary haloalkyl groups includetrifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl,and the like.

[0042] “Alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) that can comprise one or more carbon-carbon double bonds.Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl,penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl,hepten-1-yl, octen-1-yl, and the like.

[0043] “Lower alkenyl” refers to a branched or straight chain C₂-C₄hydrocarbon that can comprise one or two carbon-carbon double bonds.

[0044] “Substituted alkenyl” refers to a branched or straight chainC₂-C₁₀ hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably aC₂-C₆ hydrocarbon) which can comprise one or more carbon-carbon doublebonds, wherein one or more of the hydrogen atoms have been replaced withone or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy,an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, asdefined herein.

[0045] “Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)that can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

[0046] “Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2.1)heptyl,8-azabicyclo(3,2,1)oct-2-enyl and the like.

[0047] “Cycloalkyl” refers to a saturated or unsaturated cyclichydrocarbon comprising from about 3 to about 10 carbon atoms. Cycloalkylgroups can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl,amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid,alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo,alkylsulfinyl, and nitro. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cyclohepta-1,3-dienyl, and the like.

[0048] “Heterocyclic ring or group” refers to a saturated or unsaturatedcyclic hydrocarbon group having about 2 to about 10 carbon atoms(preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbonatoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms.Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl,furyl, thienyl, 3-pyrrolinyl, 4,5,6-trihydro-2H-pyranyl, pyridinyl,1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, andthe like.

[0049] “Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

[0050] “Aryl” refers to a monocyclic, bicyclic, carbocyclic orheterocyclic ring system comprising one or two aromatic rings. Exemplaryaryl groups include phenyl, pyridyl, napthyl, quinoyl,tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.Aryl groups (including bicyclic aryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino,arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl,hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid,alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester,alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido,alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamidoand nitro. Exemplary substituted aryl groups include tetrafluorophenyl,pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and thelike.

[0051] “Cycloalkenyl” refers to an unsaturated cyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds.

[0052] “Alkylaryl” refers to an alkyl group, as defined herein, to whichis appended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

[0053] “Arylalkyl” refers to an aryl radical, as defined herein,attached to an alkyl radical, as defined herein. Exemplary arylalkylgroups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl, and the like.

[0054] “Arylalkenyl” refers to an aryl radical, as defined herein,attached to an alkenyl radical, as defined herein. Exemplary arylalkenylgroups include styryl, propenylphenyl, and the like.

[0055] “Cycloalkylalkyl” refers to a cycloalkyl radical, as definedherein, attached to an alkyl radical, as defined herein.

[0056] “Cycloalkylalkoxy” refers to a cycloalkyl radical, as definedherein, attached to an alkoxy radical, as defined herein.

[0057] “Cycloalkylalkylthio” refers to a cycloalkyl radical, as definedherein, attached to an alkylthio radical, as defined herein.

[0058] “Heterocyclicalkyl” refers to a heterocyclic ring radical, asdefined herein, attached to an alkyl radical, as defined herein.

[0059] “Arylheterocyclic ring” refers to a bi- or tricyclic ringcomprised of an aryl ring, as defined herein, appended via two adjacentcarbon atoms of the aryl ring to a heterocyclic ring, as defined herein.Exemplary arylheterocyclic rings include dihydroindole,1,2,3,4-tetrahydroquinoline, and the like.

[0060] “Alkylheterocyclic ring” refers to a heterocyclic ring radical,as defined herein, attached to an alkyl radical, as defined herein.Exemplary alkylheterocyclic rings include 2-pyridylmethyl,1-methylpiperidin-2-one-3-methyl, and the like.

[0061] “Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, asdefined herein (preferably a lower alkyl group or a haloalkyl group, asdefined herein). Exemplary alkoxy groups include methoxy, ethoxy,t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.

[0062] “Aryloxy” refers to R₅₅O—, wherein R₅₅ is an aryl group, asdefined herein. Exemplary arylkoxy groups include napthyloxy,quinolyloxy, isoquinolizinyloxy, and the like.

[0063] “Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, asdefined herein.

[0064] “Lower alkylthio” refers to a lower alkyl group, as definedherein, appended to a thio group, as defined herein.

[0065] “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy group, asdefined herein, to which is appended an aryl group, as defined herein.Exemplary arylalkoxy groups include benzyloxy, phenylethoxy,chlorophenylethoxy, and the like.

[0066] “Alkoxyalkyl” refers to an alkoxy group, as defined herein,appended to an alkyl group, as defined herein. Exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, isopropoxymethyl, and thelike.

[0067] “Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein,appended to a haloalkyl group, as defined herein. Exemplaryalkoxyhaloalkyl groups include 4-methoxy-2-chlorobutyl and the like.

[0068] “Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl groupor a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

[0069] “Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkylgroup or a bridged cycloalkyl group, as defined herein. Exemplarycycloalkylthio groups include cyclopropylthio, cyclopentylthio,cyclohexylthio, and the like.

[0070] “Haloalkoxy” refers to an alkoxy group, as defined herein, inwhich one or more of the hydrogen atoms on the alkoxy group aresubstituted with halogens, as defined herein. Exemplary haloalkoxygroups include 1,1,1-trichloroethoxy, 2-bromobutuoxy, and the like.

[0071] “Hydroxy” refers to —OH.

[0072] “Oxo” refers to ═O.

[0073] “Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganiccation.

[0074] “Oxime” refers to ═N—OR₈₁ wherein R₈₁ is a hydrogen, an alkylgroup, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, acarboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, acarboxamido group, an alkoxyalkyl group or an alkoxyaryl group.

[0075] “Hydrazone refers to ═N—N(R₈₁)(R′₈₁) wherein R′₈₁ isindependently selected from R₈₁, and R₈₁ is as defined herein.

[0076] “Organic cation” refers to a positively charged organic ion.Exemplary organic cations include alkyl substituted ammonium cations,and the like.

[0077] “Inorganic cation” refers to a positively charged metal ion.Exemplary inorganic cations include Group I metal cations such as forexample, sodium, potassium, and the like.

[0078] “Hydroxyalkyl” refers to a hydroxy group, as defined herein,appended to an alkyl group, as defined herein.

[0079] “Nitrate” refers to —O—NO₂.

[0080] “Nitrite” refers to —O—NO.

[0081] “Thionitrate” refers to —S—NO₂.

[0082] “Thionitrite” and “nitrosothiol” refer to —S—NO.

[0083] “Nitro” refers to the group —NO₂ and “nitrosated” refers tocompounds that have been substituted therewith.

[0084] “Nitroso” refers to the group —NO and “nitrosylated” refers tocompounds that have been substituted therewith.

[0085] “Nitrile” and “cyano” refer to —CN.

[0086] “Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine(Cl), and/or fluorine (F).

[0087] “Amino” refers to —NH₂, an alkylamino group, a dialkylaminogroup, an arylamino group, a diarylamino group, an alkylarylamino groupor a heterocyclic ring, as defined herein.

[0088] “Alkylamino” refers to R₅ONH—, wherein R₅₀ is an alkyl group, asdefined herein. Exemplary alkylamino groups include methylamino,ethylamino, butylamino, cyclohexylamino, and the like.

[0089] “Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, asdefined herein.

[0090] “Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

[0091] “Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

[0092] “Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, whereinR₅₂ is an alkyl group, as defined herein, and R₅₅ is an aryl group, asdefined herein.

[0093] “Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₇₉ is an arylalkyl group, as definedherein.

[0094] “Alkylcycloalkylamino” refers to R₅₂R₈ON—, wherein R₅₂ is analkyl group, as defined herein, and R₈₀ is an cycloalkyl group, asdefined herein.

[0095] “Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

[0096] “Aminoaryl” refers to an aryl group to which is appended analkylamino group, a arylamino group or an arylalkylamino group.Exemplary aminoaryl groups include anilino, N-methylanilino,N-benzylanilino, and the like.

[0097] “Thio” refers to —S—.

[0098] “Sulfinyl” refers to —S(O)—.

[0099] “Methanthial” refers to —C(S)—.

[0100] “Thial” refers to ═S.

[0101] “Sulfonyl” refers to —S(O)₂ ⁻.

[0102] “Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen,an organic cation or an inorganic cation, as defined herein.

[0103] “Alkylsulfonic acid” refers to a sulfonic acid group, as definedherein, appended to an alkyl group, as defined herein.

[0104] “Arylsulfonic acid” refers to a sulfonic acid group, as definedherein, appended to an aryl group, as defined herein

[0105] “Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group, or an aryl heterocyclic ring, as defined herein.

[0106] “Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇are each independently a hydrogen atom, an alkyl group, an aryl group oran arylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0107] “Alkylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an alkyl group, as defined herein.

[0108] “Arylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an aryl group, as defined herein.

[0109] “Alkylthio” refers to R₅OS—, wherein R₅₀ is an alkyl group, asdefined herein (preferably a lower alkyl group, as defined herein).

[0110] “Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, asdefined herein.

[0111] “Arylalkylthio” refers to an aryl group, as defined herein,appended to an alkylthio group, as defined herein.

[0112] “Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkylgroup, as defined herein.

[0113] “Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkylgroup, as defined herein.

[0114] “Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is analkyl group, as defined herein.

[0115] “Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0116] “Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

[0117] “Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an arylgroup, as defined herein.

[0118] “Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

[0119] “Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, analkyl group, an aryl group or an arylheterocyclic ring, as definedherein.

[0120] “Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

[0121] “Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

[0122] Carbonyl” refers to —C(O)—.

[0123] “Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkylgroup, as defined herein.

[0124] “Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0125] “Arylalkylcarbonyl” refers to R₅₅—R₅₂—C(O)—, wherein R₅₅ is anaryl group, as defined herein, and R₅₂ is an alkyl group, as definedherein.

[0126] “Alkylarylcarbonyl” refers to R₅₂—R₅₅—C(O)—, wherein R₅₅ is anaryl group, as defined herein, and R₅₂ is an alkyl group, as definedherein.

[0127] “Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

[0128] “Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group or an aryl heterocyclic ring, as defined herein.

[0129] “Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkylgroup, as defined herein, appended to a carboxyl group, as definedherein.

[0130] “Alkylcarboxylic ester” refers to an alkyl group, as definedherein, appended to a carboxylic ester group, as defined herein.

[0131] “Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

[0132] “Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group,as defined herein, appended to a carboxylic ester group, as definedherein.

[0133] “Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0134] “Alkylcarboxamido” refers to an alkyl group, as defined herein,appended to a carboxamido group, as defined herein.

[0135] “Arylcarboxamido” refers to an aryl group, as defined herein,appended to a carboxamido group, as defined herein.

[0136] “Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, andR₅₉ are each independently a hydrogen atom, an alkyl group, an arylgroup or an arylheterocyclic ring, as defined herein, or R₅₁ and R₅₇taken together are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0137] “Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lonepair of electrons, thial or oxo, and R₇₁ and R₇₂ are each independentlya covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

[0138] “Silyl” refers to —Si(R₇₃)(R₇₄)(R₇₅), wherein R₇₃, R₇₄ and R₇₅are each independently a covalent bond, a lower alkyl, an alkoxy, anaryl or an arylalkoxy, as defined herein.

[0139] Compounds that donate, transfer or release nitric oxide speciesin vivo have been recognized as having a wide spectrum of advantages andapplications. The invention is based on the unexpected discovery of theeffects of such compounds alone and together with one or more COX-2inhibitors. Treatment or prevention of inflammation, pain and fever;treatment of gastrointestinal disorders and/or improvement of thegastrointestinal properties of COX-2 inhibitors; facilitation of woundhealing; and treatment and/or prevention of renal and/or respiratorytoxicity and cyclooxygenase-2 mediated disorders can be obtained by theuse of COX-2 inhibitors of the invention; or by the use of COX-2inhibitors in conjunction with one or more compounds that donate,release or transfer nitric oxide and/or stimulate endogenous productionof NO and/or EDRF in vivo and/or is a substrate for nitric oxidesynthase, and, optionally, with one or more therapeutic agents.

[0140] The COX-2 selective inhibitors, that are optionally nitrosatedand/or nitrosylated, can be used alone or in conjunction with one ormore compounds that donate, release or transfer nitric oxide and/orstimulate endogenous production of NO and/or EDRF in vivo and/or is asubstrate for nitric oxide synthase, and/or with one or more therapeuticagents, such as for example, steroids, nonsterodal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and mixturesof two or more thereof. These novel compounds and novel compositions ofthe present invention are described in more detail herein.

[0141] In one embodiment, the invention describes COX-2 inhibitors ofFormula (I), and pharmaceutically acceptable salts thereof:

[0142] wherein:

[0143] when side b is a double bond, and sides a and c are single bonds,—X¹—Y¹-Z¹- is:

[0144] (a) —CR⁴(R⁵)—CR⁵(R⁵′)—CR⁴(R⁵)—;

[0145] (b) —C(O)—CR(R⁴′)—CR⁵(R⁵′)—;

[0146] (c) —CR⁴(R⁴′)—CR⁵(R⁵′)—C(O)—;

[0147] (d) —(CR⁵(R⁵))_(k)—O—C(O)—;

[0148] (e) —C(O)—O—(CR⁵(R⁵′))_(k)—;

[0149] (f) —CR⁴(R⁴′)—NR³—CR⁵(R⁵′)—;

[0150] (g) —CR⁵(R⁵′)—NR³—C(O)—;

[0151] (h) —CR⁴═CR⁴′—S—;

[0152] (i) —S—CR⁴═CR⁴—;

[0153] (j)—S—N═CR⁴—;

[0154] (k) —CR⁴═N—S—;

[0155] (l) —N═CR⁴—O—;

[0156] (m) —O—CR⁴═N—;

[0157] (n) —NR³—CR⁴═N—;

[0158] (o) —N═CR⁴ —S—;

[0159] (p) —S—CR⁴═N—;

[0160] (q) —C(O)—NR³—CR⁵′(R⁵′)—;

[0161] (r) —R³N—CR⁵═CR⁵′—;

[0162] (s) —CR⁴═CR⁵—NR³—;

[0163] (t) —O—N═CR⁴—;

[0164] (u) —CR⁴═N—O—;

[0165] (v) —N═N—S—;

[0166] (w) —S—N═N—;

[0167] (x) —N═CR⁴—NR³—;

[0168] (y) —R³N—N═N—;

[0169] (z) —N═N—NR³—;

[0170] (aa) —CR⁴(R⁴′)—O—CR⁵(R⁵′)—;

[0171] (bb) —CR⁴(R⁴′)—S—CR⁵(R⁵′)—;

[0172] (cc) —CR⁴(R⁴′)—C(O)—CR⁵(R⁵′)—;

[0173] (dd) —CR⁴(R⁴′)—CR⁵(R⁵′)—C(S)—;

[0174] (ee) —(CR⁵(R⁵′))_(k)—O—C(S)—;

[0175] (ff) —C(S)—O—(CR⁵(R⁵′))_(k)—;

[0176] (gg) —(CR⁵(R⁵′))_(k)—NR³—C(S)—;

[0177] (hh) —C(S)—NR³—(CR⁵(R⁵′))_(k)—;

[0178] (ii) —(CR⁵(R⁵′))_(k)—S—C(O)—;

[0179] (jj) —C(O)—S—(CR⁵(R⁵′))_(k)—;

[0180] (kk) —O—CR⁴═CR⁵—;

[0181] (ll) —CR⁴═CR⁵—O—;

[0182] (mm) —C(O)—NR³—S—;

[0183] (nn) —S—NR³—C(O)—;

[0184] (oo) —C(O)—NR³—O—;

[0185] (pp) —O—NR³—C(O)—;

[0186] (qq) —NR³—CR⁴═CR⁵—;

[0187] (rr) —CR⁴═N—NR³—;

[0188] (ss) —NR³—N═CR⁴—;

[0189] (tt) —C(O)—NR³—NR³—;

[0190] (uu) —NR³—NR³—C(O)—;

[0191] (vv) —C(O)—O—NR³—;

[0192] (ww) —NR³—O—C(O)—;

[0193] (xx) —O—CR⁴R^(4′)—C(S)—;

[0194] (zz) —O—CR⁴R^(4′)—C(O)—;

[0195] (aaa) —C(S)—CR⁴R^(4′)—O—; or

[0196] (yy) —C(O)—CR⁴R^(4′)—O—;

[0197]  when sides a and c are double bonds and side b is a single bond,—X¹—Y¹-Z¹- is:

[0198] (a) ═CR⁴—O—CR⁵═;

[0199] (b) ═CR⁴—NR³—CR⁵═;

[0200] (c) ═N—S—CR⁴═;

[0201] (d) ═CR⁴—S—N═;

[0202] (e) ═N—O—CR⁴═;

[0203] (f) ═CR⁴—O—N═;

[0204] (g) ═N—S—N═;

[0205] (h) ═N—O—N═;

[0206] (i) ═N—NR³—CR⁴═;

[0207] (j) ═CR⁴—NR³—N═;

[0208] (k) ═N—NR³—N═;

[0209] (l) ═CR⁴—S—CR⁵ ═; or

[0210] (m) ═CR⁴—CR⁴(R^(4′))—CR⁵═;

[0211] R¹ is:

[0212] (a) —S(O)₂—CH₃;

[0213] (b) —S(O)₂—NR⁸(D¹);

[0214] (c) —S(O)₂—N(D¹)—C(O)—CF₃;

[0215] (d) —S(O)—(NH)—NH(D¹);

[0216] (e) —S(O)—(NH)—N(D¹)-C(O)—CF₃;

[0217] (f) —P(O)(CH₃)NH(D¹);

[0218] (g) —P(O)(CH₃)₂;

[0219] (h) —C(S)—NH(D¹);

[0220] (i) —S(O)(NH)CH₃;

[0221] (j) —P(O)(CH₃)OD¹; or

[0222] (k) —P(O)(CH₃)NH(D¹);

[0223] R^(1′) at each occurrence is independently:

[0224] (a) hydrogen;

[0225] (b) halogen;

[0226] (c) methyl; or

[0227] (d) CH₂OH;

[0228] R² is:

[0229] (a) lower alkyl;

[0230] (b) cycloalkyl;

[0231] (c) mono-, di- or tri-substituted phenyl or naphthyl, wherein thesubstituents are each independently:

[0232] (1) hydrogen;

[0233] (2) halo;

[0234] (3) alkoxy;

[0235] (4) alkylthio;

[0236] (5) CN;

[0237] (6) haloalkyl, preferably CF₃;

[0238] (7) lower alkyl;

[0239] (8) N₃;

[0240] (9) —CO₂D¹;

[0241] (10) —CO₂-lower alkyl;

[0242] (11) —(C(R⁵)(R⁶))_(z)—OD¹;

[0243] (12) —(C(R⁵)(R⁶))_(n)—O-lower alkyl;

[0244] (13) lower alkyl-CO₂—R⁵;

[0245] (14) —OD¹;

[0246] (15) haloalkoxy;

[0247] (16) amino;

[0248] (17) nitro;

[0249] (18) alkylsulfinyl; or

[0250] (19) heteroaryl;

[0251] (d) mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; wherein the substituents are each independently:

[0252] (1) hydrogen;

[0253] (2) halo;

[0254] (3) lower alkyl;

[0255] (4) alkoxy;

[0256] (5) alkylthio;

[0257] (6) CN;

[0258] (7) haloalkyl, preferably CF₃;

[0259] (8) N₃;

[0260] (9) —C(R⁵)(R⁶)—OD¹;

[0261] (10) —C(R⁵)(R⁶)—O-lower alkyl; or

[0262] (11) alkylsulfinyl;

[0263] (e) benzoheteroaryl which includes the benzo fused analogs of(d);

[0264] (f) —NR¹OR¹¹;

[0265] (g) —SR¹¹;

[0266] (h) —OR¹¹;

[0267] (i) —R¹¹;

[0268] (j) alkenyl;

[0269] (k) alkynyl;

[0270] (l) unsubstituted, mono-, di-, tri- or tetra-substitutedcycloalkenyl, wherein the substituents are each independently:

[0271] (1) halo;

[0272] (2) alkoxy;

[0273] (3) alkylthio;

[0274] (4) CN;

[0275] (5) haloalkyl, preferably CF₃;

[0276] (6) lower alkyl;

[0277] (7) N₃;

[0278] (8) —CO₂D¹;

[0279] (9) —CO₂-lower alkyl;

[0280] (10) —C(R¹²)(R¹³)—OD¹;

[0281] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0282] (12) lower alkyl-CO₂—R¹²;

[0283] (13) benzyloxy;

[0284] (14) —O-(lower alkyl)-CO₂R¹²;

[0285] (15) —O-(lower alkyl)-NR¹² R¹³; or

[0286] (16) alkylsulfinyl;

[0287] (m) mono-, di-, tri- or tetra-substituted heterocycloalkyl groupof 5, 6 or 7 members, or a benzoheterocycle, wherein saidheterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatomsselected from O, S, or N and, optionally, contains a carbonyl group or asulfonyl group, and wherein said substituents are each independently:

[0288] (1) halo;

[0289] (2) lower alkyl;

[0290] (3) alkoxy;

[0291] (4) alkylthio;

[0292] (5) CN;

[0293] (6) haloalkyl, preferably CF₃;

[0294] (7) N₃;

[0295] (8) —C(R¹²)(R¹³)—OD¹;

[0296] (9) —C(R¹²)(R¹³)—O-lower alkyl; or

[0297] (10) alkylsulfinyl;

[0298] (n) styryl, mono or di-substituted styryl, wherein thesubstituent are each independently:

[0299] (1) halo;

[0300] (2) alkoxy;

[0301] (3) alkylthio;

[0302] (4) CN;

[0303] (5) haloalkyl, preferably CF₃;

[0304] (6) lower alkyl;

[0305] (7) N₃;

[0306] (8) —CO₂D¹;

[0307] (9) —CO₂-lower alkyl;

[0308] (10) —C(R¹²)(R¹³)—OD¹;

[0309] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0310] (12) lower alkyl-CO₂—R¹²;

[0311] (13) benzyloxy;

[0312] (14) —O-(lower alkyl)-CO₂R¹²; or

[0313] (15) —O-(lower alkyl)-NR¹² R¹³;

[0314] (o) phenylacetylene, mono- or di-substituted phenylacetylene,wherein the substituents are each independently:

[0315] (1) halo;

[0316] (2) alkoxy;

[0317] (3) alkylthio;

[0318] (4) CN;

[0319] (5) haloalkyl, preferably CF₃;

[0320] (6) lower alkyl;

[0321] (7) N₃;

[0322] (8) —CO₂D¹;

[0323] (9) —CO₂-lower alkyl;

[0324] (10) —C(R¹²)(R¹³)—OD¹;

[0325] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0326] (12) lower alkyl-CO₂—R¹²;

[0327] (13) benzyloxy;

[0328] (14) —O-(lower alkyl)-CO₂R¹²; or

[0329] (15) —O-(lower alkyl)-NR¹²R¹³;

[0330] (p) fluoroalkenyl;

[0331] (q) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10members, containing 2, 3, 4 or 5 heteroatoms, wherein at least oneheteroatom resides on each ring of said bicyclic heteroaryl, saidheteroatoms are each independently O, S and N and said substituents areeach independently:

[0332] (1) hydrogen;

[0333] (2) halo;

[0334] (3) lower alkyl;

[0335] (4) alkoxy;

[0336] (5) alkylthio;

[0337] (6) CN;

[0338] (7) haloalkyl, preferably CF₃;

[0339] (8) N₃;

[0340] (9) —C(R⁵)(R⁶)—OD¹; or

[0341] (10) —C(R⁵)(R⁶)—O-lower alkyl;

[0342] (r) K;

[0343] (s) aryl;

[0344] (t) arylalkyl;

[0345] (u) cycloalkylalkyl;

[0346] (v) —C(O)R¹¹;

[0347] (u) hydrogen;

[0348] (v) arylalkenyl;

[0349] (w) arylalkoxy;

[0350] (x) alkoxy;

[0351] (y) aryloxy;

[0352] (z) cycloalkoxy;

[0353] (aa) arylthio;

[0354] (bb) alkylthio;

[0355] (cc) arylalkylthio; or

[0356] (dd) cycloalkylthio;

[0357] R³ is:

[0358] (a) hydrogen;

[0359] (b) haloalkyl, preferably CF₃;

[0360] (c) CN;

[0361] (d) lower alkyl;

[0362] (e) —(C(R_(e))(R_(f)))_(p)—U—V;

[0363] (f) K;

[0364] (g) unsubstituted or substituted:

[0365] (1) lower alkyl-Q;

[0366] (2) lower alkyl-O— lower alkyl-Q;

[0367] (3) lower alkyl-S-lower alkyl-Q;

[0368] (4) lower alkyl-O-Q;

[0369] (5) lower alkyl-S-Q;

[0370] (6) lower alkyl-O-V;

[0371] (7) lower alkyl-S-V;

[0372] (8) lower alkyl-O-K; or

[0373] (9) lower alkyl-S-K;

[0374]  wherein the substituent(s) reside on the lower alkyl group;

[0375] (h) Q;

[0376] (i) alkylcarbonyl;

[0377] (j) arylcarbonyl;

[0378] (k) alkylarylcarbonyl;

[0379] (l) arylalkylcarbonyl;

[0380] (m) carboxylic ester;

[0381] (n) carboxamido;

[0382] (o) cycloalkyl;

[0383] (p) mono-, di- or tri-substituted phenyl or naphthyl, wherein thesubstituents are each independently:

[0384] (1) hydrogen;

[0385] (2) halo;

[0386] (3) alkoxy;

[0387] (4) alkylthio;

[0388] (5) CN;

[0389] (6) haloalkyl, preferably CF₃;

[0390] (7) lower alkyl;

[0391] (8) N₃;

[0392] (9) —CO₂D¹;

[0393] (10) —CO₂-lower alkyl;

[0394] (11)—(C(R⁵)(R⁶))_(z)—OD¹;

[0395] (12) —(C(R⁵)(R⁶))_(z)—O-lower alkyl;

[0396] (13) lower alkyl-CO₂—R⁵;

[0397] (14) —OD¹;

[0398] (15) haloalkoxy;

[0399] (16) amino;

[0400] (17) nitro; or

[0401] (18) alkylsulfinyl;

[0402] (q) alkenyl;

[0403] (r) alkynyl;

[0404] (s) arylalkyl;

[0405] (t) lower alkyl-OD¹;

[0406] (u) alkoxyalkyl;

[0407] (v) aminoalkyl;

[0408] (w) lower alkyl-CO₂R¹⁰;

[0409] (x) lower alkyl-C(O)NR¹⁰(R^(10′));

[0410] (y) heterocyclicalkyl; or

[0411] (z) heterocyclic ring-C(O)—;

[0412] R⁴, R⁴′, R⁵ and R⁵′ are each independently:

[0413] (a) hydrogen;

[0414] (b) amino;

[0415] (c) CN;

[0416] (d) lower alkyl;

[0417] (e) haloalkyl;

[0418] (f) alkoxy;

[0419] (g) alkylthio;

[0420] (h) Q;

[0421] (i) —O-Q;

[0422] (j) —S-Q;

[0423] (k) K;

[0424] (l) cycloalkoxy;

[0425] (m) cycloalkylthio;

[0426] (n) unsubstituted, mono-, or di-substituted phenyl orunsubstituted, mono-, or disubstituted benzyl, wherein the substituentsare each independently:

[0427] (1) halo;

[0428] (2) lower alkyl;

[0429] (3) alkoxy;

[0430] (4) alkylthio;

[0431] (5) CN;

[0432] (6) haloalkyl, preferably CF₃;

[0433] (7) N₃;

[0434] (8) Q;

[0435] (9) nitro; or

[0436] (10) amino;

[0437] (o) unsubstituted, mono-, or di-substituted heteroaryl orunsubstituted, mono-, or di-substituted heteroarylmethyl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; said substituents are each independently:

[0438] (1) halo;

[0439] (2) lower alkyl;

[0440] (3) alkoxy;

[0441] (4) alkylthio;

[0442] (5) CN;

[0443] (6) haloalkyl, preferably CF₃;

[0444] (7) N₃;

[0445] (8) —C(R⁶)(R⁷)—OD¹;

[0446] (9) —C(R⁶)(R⁷)—O-lower alkyl; or

[0447] (10) alkylsulfinyl

[0448] (p) —CON(R⁸)(R⁸);

[0449] (q) —CH₂OR⁸;

[0450] (r) —CH₂OCN;

[0451] (s) unsubstituted or substituted:

[0452] (1) lower alkyl-Q;

[0453] (2) —O-lower alkyl-Q;

[0454] (3) —S-lower alkyl-Q;

[0455] (4) lower alkyl-O-lower alkyl-Q;

[0456] (5) lower alkyl-S-lower alkyl-Q;

[0457] (6) lower alkyl-O-Q;

[0458] (7) lower alkyl-S-Q;

[0459] (8) lower alkyl-O-K;

[0460] (9) lower alkyl-S-K;

[0461] (10) lower alkyl-O-V; or

[0462] (11) lower alkyl-S-V;

[0463]  wherein the substituent(s) resides on the lower alkyl;

[0464] (t) cycloalkyl;

[0465] (u) aryl;

[0466] (v) arylalkyl;

[0467] (w) cycloalkylalkyl;

[0468] (x) aryloxy;

[0469] (y) arylalkoxy;

[0470] (z) arylalkylthio;

[0471] (aa) cycloalkylalkoxy;

[0472] (bb) heterocycloalkyl;

[0473] (cc) alkylsulfonyloxy;

[0474] (dd) alkylsulfonyl;

[0475] (ee) arylsulfonyl;

[0476] (ff) arylsulfonyloxy;

[0477] (gg) —C(O)R¹⁰;

[0478] (hh) nitro;

[0479] (ii) amino;

[0480] (jj) aminoalkyl;

[0481] (kk) —C(O)-alkyl-heterocyclic ring;

[0482] (ll) halo;

[0483] (mm) heterocyclic ring;

[0484] (nn) —CO₂D¹;

[0485] (oo) carboxyl;

[0486] (pp) amidyl; or

[0487] (qq) alkoxyalkyl;

[0488]  alternatively, R⁴ and R⁵ together with the carbons to which theyare attached are:

[0489] (a) cycloalkyl;

[0490] (b) aryl; or

[0491] (c) heterocyclic ring;

[0492]  alternatively, R⁴ and R^(4′) or R⁵ and R^(5′) taken togetherwith the carbon to which they are attached are:

[0493] (a) cycloalkyl; or

[0494] (b) heterocyclic ring;

[0495]  alternatively, R⁴ and R⁵, R^(4′) and R^(5′), R⁴ and R^(5′)′, orR^(4′) and R⁵ when substituents on adjacent carbon atoms taken togetherwith the carbons to which they are attached are:

[0496] (a) cycloalkyl;

[0497] (b) heterocyclic ring; or

[0498] (c) aryl;

[0499] R⁶ and R⁷ are each independently:

[0500] (a) hydrogen;

[0501] (b) unsubstituted, mono- or di-substituted phenyl; unsubstituted,mono- or disubstituted benzyl; unsubstituted, mono- or di-substitutedheteroaryl; mono- or di-substituted heteroarylmethyl, wherein saidsubstituents are each independently:

[0502] (1) halo;

[0503] (2) lower alkyl;

[0504] (3) alkoxy;

[0505] (4) alkylthio;

[0506] (5) CN;

[0507] (6) haloalkyl, preferably CF₃;

[0508] (7) N₃;

[0509] (8) —C(R¹⁴)(R¹⁵)—OD¹; or

[0510] (9) —C(R¹⁴)(R¹⁵)—O-lower alkyl;

[0511] (c) lower alkyl;

[0512] (d) —CH₂OR⁸;

[0513] (e) CN;

[0514] (f) —CH₂CN;

[0515] (g) haloalkyl, preferably fluoroalkyl;

[0516] (h) —CON(R⁸)(R⁸);

[0517] (i) halo; or

[0518] (j) —OR⁸;

[0519] R⁸ is:

[0520] (a) hydrogen;

[0521] (b) K; or

[0522] (c) R⁹;

[0523]  alternatively, R⁵ and R⁵′, R⁶ and R⁷ or R⁷ and R⁸ together withthe carbon to which they are attached form a saturated monocyclic ringof 3, 4, 5, 6 or 7 atoms; optionally containing up to two heteroatomsselected from oxygen, S(O)_(o) or NR_(i);

[0524] R⁹ is:

[0525] (a) lower alkyl;

[0526] (b) lower alkyl-CO₂D¹;

[0527] (c) lower alkyl-NHD¹;

[0528] (d) phenyl or mono-, di- or tri-substituted phenyl, wherein thesubstituents are each independently:

[0529] (1) halo;

[0530] (2) lower alkyl;

[0531] (3) alkoxy;

[0532] (4) alkylthio;

[0533] (5) lower alkyl-CO₂D¹;

[0534] (6) lower alkyl-NHD¹;

[0535] (7) CN;

[0536] (8) CO₂D¹; or

[0537] (9) haloalkyl, preferably fluoroalkyl;

[0538] (e) benzyl, mono-, di- or tri-substituted benzyl, wherein thesubstituents are each independently:

[0539] (1) halo;

[0540] (2) lower alkyl;

[0541] (3) alkoxy;

[0542] (4) alkylthio;

[0543] (5) lower alkyl-CO₂D¹;

[0544] (6) lower alkyl-NHD¹;

[0545] (7) CN;

[0546] (8) —CO₂D¹; or

[0547] (9) haloalkyl, preferably CF₃;

[0548] (f) cycloalkyl;

[0549] (g) K; or

[0550] (h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein thesubstituents are each independently:

[0551] (1) halo;

[0552] (2) lower alkyl;

[0553] (3) alkoxy;

[0554] (4) alkylthio;

[0555] (5) lower alkyl-CO₂D¹;

[0556] (6) lower alkyl-NHD¹;

[0557] (7) CN;

[0558] (8) —CO₂D¹; or

[0559] (9) haloalkyl, preferably CF₃;

[0560] R¹⁰ and R¹⁰′ are each independently:

[0561] (a) hydrogen; or

[0562] (b) R¹¹;

[0563] R¹¹ is:

[0564] (a) lower alkyl;

[0565] (b) cycloalkyl;

[0566] (c) unsubstituted, mono-, di- or tri-substituted phenyl ornaphthyl, wherein the substituents are each independently:

[0567] (1) halo;

[0568] (2) alkoxy;

[0569] (3) alkylthio;

[0570] (4) CN;

[0571] (5) haloalkyl, preferably CF₃;

[0572] (6) lower alkyl;

[0573] (7) N₃;

[0574] (8) —CO₂D¹;

[0575] (9) —CO₂-lower alkyl;

[0576] (10) —C(R¹²)(R¹³)—OD¹;

[0577] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0578] (12) lower alkyl-CO₂D¹;

[0579] (13) lower alkyl-CO₂R¹²;

[0580] (14) benzyloxy;

[0581] (15) —O-(lower alkyl)-CO₂D¹;

[0582] (16) —O-(lower alkyl)-CO₂R¹²; or

[0583] (17) —O-(lower alkyl)-NR¹²R¹³;

[0584] (d) unsubstituted, mono-, di- or tri-substituted heteroaryl,wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, saidring having one heteroatom which is S, O, or N, and, optionally, 1, 2,or 3 additional N atoms; or said heteroaryl is a monocyclic ring of 6atoms, said ring having one heteroatom which is N, and, optionally 1, 2,or 3 additional N atoms, and wherein said substituents are eachindependently:

[0585] (1) halo;

[0586] (2) lower alkyl;

[0587] (3) alkoxy;

[0588] (4) alkylthio;

[0589] (5) CN;

[0590] (6) haloalkyl, preferably CF₃;

[0591] (7) N₃;

[0592] (8) —C(R¹²)(R¹³)—OD¹; or

[0593] (9) —C(R¹²)(R¹³)—O-lower alkyl;

[0594] (e) unsubstituted, mono- or di-substituted benzoheterocycle,wherein the benzoheterocycle is a 5, 6, or 7-membered ring whichcontains 1 or 2 heteroatoms independently selected from O, S, or N, and,optionally, a carbonyl group or a sulfonyl group, wherein saidsubstituents are each independently:

[0595] (1) halo;

[0596] (2) lower alkyl;

[0597] (3) alkoxy;

[0598] (4) alkylthio;

[0599] (5) CN;

[0600] (6) haloalkyl, preferably CF₃;

[0601] (7) N₃;

[0602] (8) —C(R¹²)(R¹³)—OD¹; or

[0603] (9) —C(R¹²)(R¹³)—O-lower alkyl;

[0604] (f) unsubstituted, mono- or di-substituted benzocarbocycle,wherein the carbocycle is a 5, 6, or 7-membered ring which optionallycontains a carbonyl group, wherein said substituents are eachindependently:

[0605] (1) halo;

[0606] (2) lower alkyl;

[0607] (3) alkoxy;

[0608] (4) alkylthio;

[0609] (5) CN;

[0610] (6) haloalkyl, preferably CF₃;

[0611] (7) N₃;

[0612] (8) —C(R¹²)(R¹³)—OD¹; or

[0613] (9) —C(R¹²)(R¹³)—O-lower alkyl;

[0614] (g) hydrogen; or

[0615] (h) K

[0616] R¹² and R¹³ are each independently:

[0617] (a) hydrogen;

[0618] (b) lower alkyl; or

[0619] (c) aryl; or

[0620] R¹² and R¹³ together with the atom to which they are attachedform a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

[0621] R¹⁴ and R¹⁵ are each independently:

[0622] (a) hydrogen; or

[0623] (b) lower alkyl; or

[0624] R¹⁴ and R¹⁵ together with the atom to which they are attachedform a carbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6or 7 atoms;

[0625] Q is:

[0626] (a) —C(O)—U-D¹;

[0627] (b) —CO₂-lower alkyl;

[0628] (c) tetrazolyl-5-yl;

[0629] (d) —C(R⁷)(R⁸)(S-D¹);

[0630] (e) —C(R⁷)(R⁸)(O-D¹); or

[0631] (f) —C(R⁷)(R⁸)(O-lower alkyl);

[0632] X⁵ is:

[0633] (a) —(CR³¹R³²)_(a)—;

[0634] (b) —(CR³¹R³²)_(bb)-A¹;

[0635] (c) —A¹-(CR³¹R³²)_(bb)—;

[0636] (d) —CR³¹R³²-A¹CR³¹R³²;

[0637] (e) —CR³¹═; or

[0638] (f) -A;

[0639] A¹ is:

[0640] (a) oxygen;

[0641] (b) thio;

[0642] (c) sulfinyl;

[0643] (d) sulfonyl; or

[0644] (c) —N(R³³)—;

[0645] R³¹ and R³² are each independently:

[0646] (a) hydrogen;

[0647] (b) lower alkyl;

[0648] (c) substituted lower alkyl;

[0649] (d) lower alkoxy;

[0650] (e) lower haloalkyl; or

[0651] (f) halo; or

[0652] R³¹ and R³² taken together are;

[0653] (a) oxo;

[0654] (b) thial;

[0655] (c) oxime; or

[0656] (d) hydrazone;

[0657] R³³ is:

[0658] (a) lower alkyl;

[0659] (b) hydrogen; or

[0660] (c) —C(O)H;

[0661] a is an integer equal to 1 or 3;

[0662] bb is an integer equal to 2 or 3;

[0663] D¹ is:

[0664] (a) hydrogen or

[0665] (b) D;

[0666] D is:

[0667] (a) V; or

[0668] (b) K;

[0669] U is:

[0670] (a) oxygen;

[0671] (b) sulfur; or

[0672] (c) —N(R_(a))(R_(i))—;

[0673] V is:

[0674] (a) —NO;

[0675] (b) —NO₂; or

[0676] (c) hydrogen

[0677] K is-W_(aa)-E_(b)-(C(R_(e))(R_(f)))_(p)-E_(c)-(C(R_(e))(R_(f)))_(x)-W_(d)-(C(R_(e))(R_(f)))_(y)-W_(i)-E_(j)-W_(g)-(C(R_(e))(R_(f)))_(z)—U—V;

[0678] wherein aa, b, c, d, g, i and j are each independently an integerfrom 0 to 3;

[0679] p, x, y and z are each independently an integer from 0 to 10;

[0680] W at each occurrence is independently:

[0681] (a) —C(O)—;

[0682] (b) —C(S)—;

[0683] (c) -T-;

[0684] (d) —(C(R_(e))(R_(f)))_(h)—;

[0685] (e) alkyl;

[0686] (f) aryl;

[0687] (g) heterocyclic ring;

[0688] (h) arylheterocyclic ring, or

[0689] (i) —(CH₂CH₂O)_(q)—;

[0690] E at each occurrence is independently a -T- group, an alkylgroup, an aryl group, a heterocyclic ring, —(C(R_(e))(R_(f)))_(h)—, anarylheterocyclic ring or —(CH₂CH₂O)_(q)—;

[0691] h is an integer form 1 to 10;

[0692] q is an integer from 1 to 5;

[0693] R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, analkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, anarylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, ahaloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, anarylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, anaminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, aalkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, acarbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl,an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, anitro, -T-Q′-, or —(C(R_(g))(R_(h)))_(k)-T-Q′ or R_(e) and R_(f) takentogether are an oxo, a thial, a heterocyclic ring, a cycloalkyl group,an oxime, a hydrazone or a bridged cycloalkyl group;

[0694] Q′ is —NO or —NO₂;

[0695] k is an integer from 1 to 3;

[0696] T is independently a covalent bond, a carbonyl, an oxygen,—S(O)_(o)— or —N(R_(a))R_(i)—,

[0697] o is an integer from 0 to 2,

[0698] R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;

[0699] R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid,an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylicester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, analkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy,an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, anaminoalkyl, an aminoaryl, —OR′_(i), —CH₂—C(T-Q′)(R_(g))(R_(h)), a bondto an adjacent atom creating a double bond to that atom or —(N₂O₂—)⁻.M⁺,wherein M⁺ is an organic or inorganic cation; with the proviso that whenR_(i) is —CH₂—C(T-Q′)(R_(g))(R_(h)) or —(N₂O₂—).M⁺; then “-T-Q′” can bea hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group;

[0700] R_(g) and R_(h) at each occurrence are independently R_(e);

[0701] R′_(i) is independently selected from R_(i).

[0702] In cases where R_(e) and R_(f) are a heterocyclic ring or R_(e)and R_(f) taken together with the carbon atom to which they are attachedare a heterocyclic ring, then R_(i) can be a substituent on anydisubstituted nitrogen contained within the radical where R_(i) is asdefined herein.

[0703] In cases where multiple designations of variables that reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E-E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

[0704] Another embodiment of the invention describes compounds ofFormula (II) and pharmaceutically acceptable salts thereof:

[0705] wherein:

[0706] A-B is:

[0707] (a) N—C;

[0708] (b) C—N; or

[0709] (c) N—N;

[0710] when A-B is N—C, sides d and f are double bonds, and sides e andg are single bonds, X²—Y²-Z²- is:

[0711] (a) ═CR⁴—CR⁴′═CR⁵—;

[0712] (b) ═N—CR⁴═CR⁴′;

[0713] (c) ═N—CR⁴═N—;

[0714] (d) ═CR⁴—N═CR⁴′—;

[0715] (e) ═CR⁴—N═N—;

[0716] (f) ═N—N═CR⁴—;

[0717] (g) ═N—N═N—; or

[0718] (h) ═CR⁴—CR⁵═N—;

[0719] when A-B is C—N, sides e and g are double bonds, and sides d andf are single bonds, —X²—Y²-Z²- is:

[0720] (a) —CR⁴═N—N═;

[0721] (b) —N═N—CR⁴═;

[0722] (c) —CR⁴═N—CR⁴′═;

[0723] (d) —N═CR⁴—N═;

[0724] (e) —CR⁴═CR⁴′—N═;

[0725] (f) —N═CR⁴—CR⁵═;

[0726] (g) —CR⁴═CR⁵—CR^(5′)═; or

[0727] (h) —N═N—N═;

[0728] when A-B is C—N, side g is a double bond, and sides d, e and fare single bonds, —X²—Y²-Z²- is:

[0729] (a) —C(O)—O—CR⁴═;

[0730] (b) —C(O)—NR³—CR⁴═;

[0731] (c) —C(O)—S—CR⁴═; or

[0732] (d) —C(H)R⁴—C(OH)R⁵—N═;

[0733] when A-B is N—C, sides d is a double bond, and sides e, f and gare single bonds, —X²—Y²-Z²- is:

[0734] (a) ═CR⁴—O—C(O)—;

[0735] (b) ═CR⁴—NR³—C(O)—;

[0736] (c) ═CR⁴—S—C(O)—; or

[0737] (d) ═N—C(OH)R⁴—C(H)R⁵—;

[0738] when sides f is a double bond, and sides d, e and g are singlebonds, —X²—Y¹-Z¹- is:

[0739] (a) —CH(R⁴)—CR⁵═N—; or

[0740] (b) —C(O)—CR⁴═CR⁵—;

[0741] when sides e is a double bond, and sides d, f and g are singlebonds, —X²—Y²-Z²- is:

[0742] (a) —N═CR⁴—CH(R⁵)—; or

[0743] (b) —CR⁴═CR⁵—C(O)—;

[0744] when sides d, e, f and g are single bonds, —X²—Y²-Z²- is:

[0745] (a) —C(O)—CR⁴(R^(4′))—C(O)—; and

[0746] with the proviso that when A-B is C—N, then X⁵ must be—(CR³¹R³²)_(a) or —(CR³¹R³²)_(bb)-A¹; and

[0747] wherein R, R^(1′), R², R³, R⁴, R⁴′, R⁵, R⁵′, X⁵ A¹, R³¹, R³², aand bb are as defined herein

[0748] Another embodiment of the invention describes compounds ofFormula (III) and pharmaceutically acceptable salts thereof:

[0749] wherein:

[0750] X³ is:

[0751] (a) —C(O)—U-D¹;

[0752] (b) —CH₂—U-D¹;

[0753] (c) —CH₂—C(O)—CH₃;

[0754] (d) —CH₂—CH₂—C(O)—U-D¹;

[0755] (e) —CH₂—O-D¹;

[0756] (f) —C(O)H or

[0757] (g) c(O)—U-R¹²;

[0758] Y³ is:

[0759] (a) —(CR⁵(R⁵′))_(k)—U-D¹;

[0760] (b) —CH₃;

[0761] (c) —CH₂OC(O)R⁶; or

[0762] (d) —C(O)H;

[0763] R⁸², R^(82′), R⁸³ and R^(83′) are each independently:

[0764] (a) hydrogen;

[0765] (b) hydroxy;

[0766] (c) alkyl;

[0767] (d) alkoxy;

[0768] (e) lower alkyl-OD¹;

[0769] (f) alkylthio;

[0770] (g) CN;

[0771] (h) —C(O)R⁸⁴; or

[0772] (i) —OC(O)R⁸⁵;

[0773] R⁸⁴ is:

[0774] (a) hydrogen;

[0775] (b) lower alkyl; or

[0776] (c) alkoxy;

[0777] R⁸⁵ is:

[0778] (a) lower alkyl;

[0779] (b) alkoxy

[0780] (c) unsubstituted, mono-, di- or tri-substituted phenyl orpyridyl, wherein the substituents are each independently:

[0781] (1) halo;

[0782] (2) alkoxy;

[0783] (3) haloalkyl;

[0784] (4) CN;

[0785] (5) —C(O)R⁸⁴;

[0786] (6) lower alkyl;

[0787] (7) —S(O)_(o)-lower alkyl; or

[0788] (8) —OD¹;

[0789] alternatively, R⁸² and R⁸³ or R^(8′) and R^(83′) taken togetherare:

[0790] (a) oxo;

[0791] (b) thial;

[0792] (c) ═CR⁸⁶R⁸⁷; or

[0793] (d) ═NR⁸⁸;

[0794] R⁸⁶ and R⁸⁷ are each independently:

[0795] (a) hydrogen;

[0796] (b) lower alkyl;

[0797] (c) lower alkyl-OD¹;

[0798] (d) CN; or

[0799] (e) —C(O)R⁸⁴;

[0800] R⁸⁸ is:

[0801] (a) OD¹;

[0802] (b) alkoxy;

[0803] (c) lower alkyl; or

[0804] (d) unsubstituted, mono-, di- or tri-substituted phenyl orpyridyl, wherein the substituents are each independently:

[0805] (1) halo;

[0806] (2) alkoxy;

[0807] (3) haloalkyl;

[0808] (4) CN;

[0809] (5) —C(O)R⁸⁴;

[0810] (6) lower alkyl;

[0811] (7) —S(O)O-lower alkyl; or

[0812] (8) —OD¹;

[0813] X⁶ is:

[0814] (a) —(CR³¹R³²)_(a)—;

[0815] (b) —(CR³¹R³²)_(bb)-A¹-; or

[0816] (e) —CR³¹═; and

[0817] wherein R¹, R^(1′), R², R⁵, R⁵′, R⁶, R¹², R³¹, R³², A¹, U, D¹, a,bb, o and k are as defined herein.

[0818] Another embodiment of the invention describes compounds ofFormula (IV) and pharmaceutically acceptable salts thereof:

[0819] wherein:

[0820] X⁴ and Z⁴ are each independently:

[0821] (a) N; or

[0822] (b) CR²¹;

[0823] R²⁰ is:

[0824] (a) —S(O)₂—CH₃;

[0825] (b) —S(O)₂—NR⁸(D¹); or

[0826] (c) —S(O)₂—N(D¹)-C(O)—CF₃;

[0827] R²¹ and R^(21′) are each independently:

[0828] (a) hydrogen;

[0829] (b) lower alkyl;

[0830] (c) alkoxy;

[0831] (d) alkylthio;

[0832] (e) haloalkyl, preferably fluoroalkyl;

[0833] (f) haloalkoxy, preferably fluoroalkoxy;

[0834] (g) CN;

[0835] (h) —CO₂D¹;

[0836] (i) —CO₂R¹⁴;

[0837] (j) lower alkyl-O-D¹;

[0838] (k) lower alkyl-CO₂D¹;

[0839] (l) lower alkyl-CO₂R¹⁴;

[0840] (m) halo;

[0841] (n) —O-D¹;

[0842] (o) —N₃;

[0843] (p) —NO₂;

[0844] (q) —NR¹⁴D¹;

[0845] (r) —N(D¹)C(O)R¹⁴;

[0846] (s) —NHK;

[0847] (t) aryl;

[0848] (u) arylalkylthio;

[0849] (v) arylalkoxy;

[0850] (w) alkylamino;

[0851] (x) aryloxy;

[0852] (y) alkylarylalkylamino;

[0853] (z) cycloalkylalkylamino; or

[0854] (aa) cycloalkylalkoxy;

[0855] R²² is:

[0856] (a) mono-, di- or tri-substituted phenyl or pyridinyl (or theN-oxide thereof), wherein the substituent are each independently:

[0857] (1) hydrogen;

[0858] (2) halo;

[0859] (3) alkoxy;

[0860] (4) alkylthio;

[0861] (5) CN;

[0862] (6) lower alkyl;

[0863] (7) haloalkyl, preferably fluoroalkyl;

[0864] (8) N₃;

[0865] (9) —CO₂D¹;

[0866] (10) —CO₂-lower alkyl;

[0867] (11)—C(R¹⁴)(R¹⁵)—OD¹;

[0868] (12) —OD¹;

[0869] (13) lower alkyl-CO₂—R¹⁴; or

[0870] (14) lower alkyl-CO₂-D¹;

[0871] (b) -T-C(R²³)(R²⁴)—(C(R²⁵)(R²⁶))_(o)—C(R²⁷)(R²⁸)—U-D¹;

[0872] (d) arylalkyl; or

[0873] (e) cycloalkylalkyl;

[0874] wherein:

[0875] R¹⁴ and R¹⁵ are each independently:

[0876] (a) hydrogen; or

[0877] (b) lower alkyl;

[0878] R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ are each independently:

[0879] (a) hydrogen; or

[0880] (b) lower alkyl; or

[0881] R²³ and R²⁷, or R²⁷ and R²⁸ together with the atoms to which theyare attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R²³and R²⁵ are joined to form a covalent bond;

[0882] Y⁵ is:

[0883] (a) CR²⁹R³⁰;

[0884] (b) oxygen; or

[0885] (c) sulfur;

[0886] R²⁹ and R³⁰ are each independently:

[0887] (a) hydrogen;

[0888] (b) lower alkyl;

[0889] (c) (CH₂)_(o)—OD¹;

[0890] (d) halo; or

[0891] R²⁹ and R³⁰ taken together are an oxo group;

[0892] s is an integer from 2 to 4; and

[0893] wherein R^(1′), R⁸, X⁵, D¹, T, U, K and o are as defined herein.

[0894] Another embodiment of the invention describes compounds ofFormula (V) and pharmaceutically acceptable salts thereof:

[0895] wherein:

[0896] X⁷ is:

[0897] (a) oxygen;

[0898] (b) sulfur;

[0899] (c) —NR⁵¹;

[0900] (d) —N—O—R⁵²; or

[0901] (e) —N—NR⁵²R⁵²;

[0902] Y⁷ at each occurrence is independently:

[0903] (a) hydrogen;

[0904] (b) halo;

[0905] (c) lower alkyl;

[0906] (d) alkenyl; or

[0907] (e) alkynyl;

[0908] Z⁷ is:

[0909] (a) —(CR³R³²)_(a)—;

[0910] R⁴⁹ is:

[0911] (a) R³; or

[0912] (b) R⁴;

[0913] R⁵⁰ and R^(50′) are each independently:

[0914] (a) hydrogen;

[0915] (b) halo;

[0916] (c) lower alkyl;

[0917] (d) aryl;

[0918] (e) arylalkyl;

[0919] (f) cycloalkyl;

[0920] (g) cycloalkylalkyl;

[0921] (h) —OD¹;

[0922] (i) lower alkyl-OD¹;

[0923] (j) carboxamido;

[0924] (k) amidyl; or

[0925] (l) K;

[0926] R⁵¹ is:

[0927] (a) lower alkyl;

[0928] (b) alkenyl;

[0929] (c) cycloalkyl;

[0930] (d) cycloalkylalkyl;

[0931] (e) aryl;

[0932] (f) arylalkyl;

[0933] (g) heterocyclic ring; or

[0934] (h) lower alkyl-heterocyclic ring;

[0935] R⁵² and R⁵³ are each independently:

[0936] (a) lower alkyl;

[0937] (b) cycloalkyl;

[0938] (c) cycloalkylalkyl;

[0939] (d) aryl;

[0940] (e) arylalkyl;

[0941] (f) heterocyclic ring; or

[0942] (g) heterocyclicalkyl; and

[0943] wherein R¹, R³, R⁴, R³¹, R³², K, D¹ and a are as defined herein.

[0944] Another embodiment of the invention describes compounds of theFormula (VI) and pharmaceutically acceptable salts thereof:

[0945] wherein:

[0946] X⁹ is —C(O)—U-D¹ and Y⁹ is —CH₂—CR⁵(R⁵′)—U-D¹; or

[0947] X⁹ is —CH₂—CR⁵(R⁵′)—U-D¹ and Y⁹ is —C(O)—U-D¹; or

[0948] X⁹ and Y⁹ taken together are:

[0949] (a) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[0950] (b) —(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—CR⁵(R^(5′))—;

[0951] (c) —C(O)—(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—;

[0952] (d) —(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—C(O)—; or

[0953] (e) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[0954] wherein X⁹ is the first carbon atom of a, b, c, d and e; and

[0955] wherein R¹, R^(1′), R², R⁴, R⁴′, R⁵, R⁵′, X⁶, U, D¹ and k are asdefined herein.

[0956] Another embodiment of the invention describes compounds of theFormula (VII) and pharmaceutically acceptable salts thereof:

[0957] wherein:

[0958] when side h, k, and j are single bonds, and side i and l are adouble bond, —X¹⁰—Y¹⁰-Z¹⁰- is:

[0959] when sides i, k and l are single bonds, and sides h and j aredouble bonds, —X¹⁰—Y¹⁰-Z¹⁰- is:

[0960] when side h and j are single bonds, l is a double bond, and sidek and i is a single or a double bond, —X¹⁰—Y¹⁰-Z¹⁰- is:

[0961] p¹⁰ is:

[0962] (a) —N═;

[0963] (b) —NR³—;

[0964] (c) —O—; or

[0965] (d) —S—;

[0966] Q¹⁰ and Q^(10′) are each independently:

[0967] (a) CR⁶⁰; or

[0968] (b) nitrogen;

[0969] A¹⁰-B¹⁰-C¹⁰-D¹⁰- is:

[0970] (a) —CR⁴═CR^(4′)—CR⁵═CR^(5′)—;

[0971] (b) —CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—C(O)—;

[0972] (c) —CR⁴(R⁴′)—CR⁵(R^(5′))—C(O)—CR⁴(R^(4′))—;

[0973] (d) —CR⁴(R^(4′))—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[0974] (e) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—;

[0975] (f) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

[0976] (g) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—;

[0977] (h) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[0978] (i) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—C(O)—;

[0979] (j)—CR⁴(R^(4′))—O—C(O)—CR⁵(R^(5′));

[0980] (k) —O—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[0981] (l) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—O—;

[0982] (m) —CR⁴(R^(4′))—C(O)—O—CR⁵(R^(5′))—;

[0983] (n) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[0984] (o) —CR¹²(R¹³)—O—C(O)—;

[0985] (p) —C(O)—O—CR¹²(R¹³)—;

[0986] (q) —O—C(O)—CR¹²(R¹³)—;

[0987] (r) —CR¹² (R¹³)C(O)—O—;

[0988] (s) —N═CR⁴—CR^(4′)═CR⁵—;

[0989] (t) —CR⁴═N—CR^(4′)═CR⁵;

[0990] (u) —CR⁴═CR^(4′)—N═CR⁵;

[0991] (v) —CR⁴═CR⁵—CR^(5′)═N—;

[0992] (w) —N═CR⁴—CR^(4′)═N—;

[0993] (x) —N═CR⁴—N═CR^(4′)—;

[0994] (y) —CR⁴═N—CR^(4′)═N—;

[0995] (z) —S—CR⁴═N—;

[0996] (aa) —S—N═CR⁴—;

[0997] (bb) —N═N—NR³—;

[0998] (cc) —CR⁴═N—S—;

[0999] (dd) —N═CR⁴—S—;

[1000] (ee) —O—CR⁴═N—;

[1001] (ff) —O—N═CR⁴—; or

[1002] (gg) —N═CR⁴—O—;

[1003] A¹⁰′-B¹⁰′-D¹⁰′ is:

[1004] (a) —CR⁴═CR⁵—CR^(5′)═

[1005] (b) —CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—;

[1006] (c) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1007] (d) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

[1008] (e) —N═CR⁴—CR⁵═;

[1009] (g) —N═N—CR⁴═;

[1010] (h) —N═N—NR³—;

[1011] (i) —N═N—N═;

[1012] (j) —N═CR⁴—NR³—;

[1013] (k) —N═CR⁴—N═;

[1014] (l) —CR⁴═N—NR³—;

[1015] (m) —CR⁴═N—N═;

[1016] (n) —CR⁴═N—CR⁵═;

[1017] (o) —CR⁴═CR⁵—NR³—;

[1018] (p) —CR⁴═CR⁵—N═;

[1019] (q) —S—CR⁴═CR⁵—;

[1020] (r) —O—CR⁴═CR⁵;

[1021] (s) —CR⁴═CR⁵—O—;

[1022] (t) —CR⁴═CR⁵—S—;

[1023] (u) —CR⁴═N—S—;

[1024] (v) —CR⁴═N—O—;

[1025] (w) —N═CR⁴—S—;

[1026] (x) —N═CR⁴—O—;

[1027] (y) —S—CR⁴═N—;

[1028] (z) —O—CR⁴═N—;

[1029] (aa) —N═N—S—;

[1030] (bb) —N═N—O—;

[1031] (cc) —S—N═N—;

[1032] (dd) —O—N═N—;

[1033] (ee) —CR⁴═CR⁵—S;

[1034] (ff) —CR⁴(R^(4′))—CR⁵(R^(5′))—S—;

[1035] (gg) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—;

[1036] (hh) —S—CR⁴(R^(4′))—CR⁵(R^(5′))—; or

[1037] (ii) —O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1038] R⁶⁰ and R⁶¹ are each independently:

[1039] (a) lower alkyl;

[1040] (b) haloalkyl, preferably fluoroalkyl;

[1041] (c) alkoxy;

[1042] (d) alkylthio;

[1043] (e) lower alkyl-OD¹;

[1044] (f) —C(O)H;

[1045] (h) —(CH₂)_(q)—CO₂-lower alkyl;

[1046] (i) —(CH₂)_(q)—CO₂D¹;

[1047] (j) —O—(CH₂)_(q)—S-lower alkyl;

[1048] (k) —(CH₂)_(q)—S-lower alkyl;

[1049] (l) —S(O)₂-lower alkyl;

[1050] (m) —(CH₂)_(q)—NR¹²R¹³; or

[1051] (n) —C(O)N(R⁸)(R⁸); and

[1052] wherein R¹, R^(1′), R², R³, R⁴, R^(4′), R⁵, R^(5′), R⁸, R¹², R¹³,X⁵, T, D¹ and q are as defined herein.

[1053] Another embodiment of the invention describes compounds of theFormula (VIII) and pharmaceutically acceptable salts thereof:

[1054] wherein:

[1055] X¹⁴ is:

[1056] (a) —C(O)—; or

[1057] (b) —C(S)—;

[1058] Y¹⁴ is:

[1059] (a) —O—; or

[1060] (b) —S—;

[1061] A¹⁴-B¹⁴-D¹⁴- is:

[1062] (a) —CR⁴═CR^(4′)—CR⁵═CR^(5′)—;

[1063] (b) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

[1064] (c) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—;

[1065] (d) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1066] (e) —CR⁴(R⁵)—O—C(O)—;

[1067] (f) —C(O)—O—CR⁴(R⁵)—;

[1068] (g) —O—C(O)—CR⁴(R⁵)—;

[1069] (h) —S—N═CR⁴—;

[1070] (i) —O—N═CR⁴—;

[1071] (j)—CR⁴(R⁵)—NR³—C(O)—;

[1072] (k) —C(O)—NR³—CR⁴(R⁵)—;

[1073] (l) —NR³—C(O)—CR⁴(R⁵)—;

[1074] (m) —CR⁴(R⁵)—S—C(O)—;

[1075] (n) —C(O)—S—CR⁴(R⁵)—;

[1076] (o) —S—C(O)—CR⁴(R⁵)—;

[1077] (p) —CR⁴═CR⁴—C(O)—;

[1078] (q) —C(O)—CR⁴═CR^(4′)—;

[1079] (r) —O—CR⁴═CR^(4′)—;

[1080] (s) —S—CR⁴═CR^(4′)—;

[1081] (t) —NR³—CR⁴═CR⁵—;

[1082] (u) —S—NR³—C(O)—;

[1083] (v) —O—NR³—C(O)—; or

[1084] (w) —NR³—N═CR⁴—; and

[1085] wherein R¹, R^(1′), R², R³, R⁴, R^(4′), R⁵, R^(5′) and X⁵ are asdefined herein.

[1086] In another embodiment of the invention describes compounds ofFormulas (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), andpharmaceutically acceptable salts thereof, that each must contain atleast one NO and/or NO₂ group (i.e., nitrosylated and/or nitrosated)wherein the one NO and/or NO₂ group is linked to the compounds ofFormula (I) to (VIII) through one or more sites, such as oxygen(hydroxyl condensation), sulfur (sulfhydryl condensation) and/ornitrogen.

[1087] Another embodiment of the invention describes the metabolites ofthe compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII) and(VIII), and pharmaceutically acceptable salts thereof. Thesemetabolites, include but are not limited to, the non-nitrosated and/ornormitrosylated derivatives, degradation products, hydrolysis products,and the like, of the compounds of Formulas (I), (II), (III), (IV), (V),(VI), (VII), and (VIII), and pharmaceutically acceptable salts thereof.

[1088] In other embodiments of the invention, the COX-2 selectiveinhibitors of Formula II are:

[1089]1-(1-(cyclohexylmethyl)-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1090]4-(1-(cyclohexylmethyl)-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;

[1091]1-(3-(hydroxymethyl)-1-benzylpyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1092]1-(3-((1E)-3-Hydroxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1093]1-(1-(cyclohexylmethyl)-3-(3-hydroxypropyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1094]1-(1-(cyclohexylmethyl)-3-vinylpyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1095] methyl(2E)-3-(1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)prop-2-enoate;

[1096] methyl5-(4-(methylsulfonyl)phenyl)-1-benzylpyrazole-3-carboxylate; andpharmaceutically acceptable salts thereof.

[1097] In other embodiments of the invention, the nitrosated COX-2selective inhibitors of Formula II are:

[1098]1-(1-(cyclohexylmethyl)-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1099]4-(1-(cyclohexylmethyl)-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;

[1100]4-(methylsulfonyl)-1-(3-((nitrooxyl)methyl)-1-benzylpyrazol-5-yl)benzene;

[1101]1-(3-((1E)-3-nitrooxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

[1102]1-(1-(cyclohexylmethyl)-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; and pharmaceutically acceptable salts thereof.

[1103] In other embodiments of the invention, the COX-2 selectiveinhibitors of Formula IV are:

[1104] 3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl)phenyl ketone;

[1105]2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrile;

[1106] 3-fluorophenyl 2-(4-methylsulfonylphenyl)(3-pyridyl) ketone;

[1107] 2-(4-(methylsulfonyl)phenyl)(3-pyridyl) 2-pyridyl ketone;

[1108] ethyl3-((2-(4-(methylsulfonyl)phenyl)-3-pyridyl)carbonyl)benzoate; andpharmaceutically acceptable salts thereof.

[1109] Compounds of the invention that have one or more asymmetriccarbon atoms may exist as the optically pure enantiomers, purediastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The invention includes within its scope allsuch isomers and mixtures thereof.

[1110] Another embodiment of the invention provides processes for makingthe novel compounds of the invention and to the intermediates useful insuch processes. The reactions are performed in solvents appropriate tothe reagents and materials used are suitable for the transformationsbeing effected. It is understood by one skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

[1111] The chemical reactions described herein are generally disclosedin terms of their broadest application to the preparation of thecompounds of this invention. Occasionally, the reactions may not beapplicable as described to each compound included within the disclosedscope. The compounds for which this occurs will be readily recognized byone skilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

[1112] The intermediates for the compounds of Formulas (I), (II), (III),(IV), (V), (VI), (VII) and (VIII) can be synthesized by one skilled inthe art following the methods and examples described herein. Thesynthesis of the intermediates for the COX-2 inhibitors (i.e.non-nitrosated and/or non-nitrosylated COX-2 inhibitors) are disclosedin, for example, U.S. Pat. Nos. 5,344,991, 5,393,790, 5,466,823,5,474,995, 5,486,534, 5,504,215, 5,508,426, 5,510,496, 5,516,907,5,521,207, 5,536,752, 5,550,142, 5,563,165, 5,616,601, 5,620,999,5,677,318, 5,668,161, 5,691,374, 5,698,584, 5,710,140, 5,753,688,5,859,257, 5,908,858, 5,945,539, 5,994,381, 6,080,876, 6,083,969 and6,071,954 and in WO 91/19708, WO 94/15932, WO 94/26731, WO 94/27980, WO95/00501, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO95/15318, WO 95/18799, WO 95/21817, WO 95/30652, WO 96/30656, WO96/03387, WO 96/03392, WO 96/03385, WO 96/03387, WO 96/03388, WO96/09293, WO 96/09304, WO 96/16934, WO 96/19462, WO 96/19463, WO96/19469, WO 96/25405, WO 96/36617, WO 96/36623, WO 97/11704, WO97/13755, WO 97/27181, WO 97/14691, WO 97/16435, WO 97/34882, WO97/36863, WO 97/40012, WO 97/45420, WO 98/00416, WO 98/11080, WO98/22422, WO 98/41516, WO 98/46594, WO 98/52937, WO 99/15531, WO99/23087, WO 99/33796, WO 99/25695, WO 99/61016, WO 99/62884 and WO99/64415 and in EP 0 745 596 A1, EP0087 629B1, EP0418 845B1,EP0554829A2, EP0863 134A1, EP 1 006 114A1 for the intermediate ofFormulas (I) and (II); and in U.S. Pat. Nos. 5,733,909, 5,789,413 and5,849,943 and in WO 96/13483, WO 97/28120 and WO 97/28121 for theintermediates of Formula (III); and in U.S. Pat. No. 5,861,419 and6,001,843 and in WO 96/10012, WO 96/16934, WO 96/24585, WO 98/03484, WO98/24584, WO 98/47871, WO 99/14194 and WO 99/14195 for the intermediatesof Formula (IV); and in WO 98/41511, WO 99/10331, WO 99/10332 and WO00/24719 for the intermediates of Formula (V); and in U.S. Pat. No.5,807,873 and WO 98/43966 for the intermediates of Formula (VI); and inU.S. Pat. Nos. 5,521,213 and 5,552,422 and in WO 96/06840, WO 96/21667,WO 96/31509, WO 99/12930, WO 00/08024 and WO 00/26216 for theintermediates of Formula (VII); and in WO 00/10993 for the intermediatesof Formula (XIV); and in WO 98/32732 for the intermediates of Formula(VII); the disclosures of each of which are incorporated by referenceherein in their entirety. The COX-2 inhibitor compounds can then benitrosated and/or nitrosylated through one or more sites such as oxygen,sulfur and/or nitrogen using the methods described in the examplesherein and using conventional methods known to one skilled in the art.For example, known methods for nitrosating and/or nitrosylatingcompounds are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO94/03421, WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641, WO97/27749, WO 98/19672, WO 00/25776, WO 01/00563 and WO 01/04082, WO01/10814, WO 01/45703 and Oae et al, Org. Prep. Proc. Int.,15(3):165-198 (1983), the disclosures of each of which are incorporatedby reference herein in their entirety. The methods of nitrosating and/ornitrosylating the compounds described in the examples herein and inthese references can be applied by one skilled in the art to produce anyof the nitrosated and/or nitrosylated COX-2 inhibitors described herein.

[1113] The compounds of the invention include the COX-2 inhibitors,which have been nitrosated and/or nitrosylated through one or more sitessuch as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation)and/or nitrogen. The nitrosated and/or nitrosylated COX-2 inhibitors ofthe invention donate, transfer or release a biologically active form ofnitrogen monoxide (i.e., nitric oxide).

[1114] Nitrogen monoxide can exist in three forms: NO− (nitroxyl), NO.(uncharged nitric oxide) and NO⁺ (nitrosonium). NO. is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO.),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO− arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

[1115] Compounds contemplated for use in the invention, e.g., COX-2selective inhibitor, that can be optionally nitrosated and/ornitrosylated, through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen, are,optionally, used in combination with nitric oxide and compounds thatrelease nitric oxide or otherwise directly or indirectly deliver ortransfer a biologically active form of nitrogen monoxide to a site ofits intended activity, such as on a cell membrane in vivo.

[1116] The term “nitric oxide” encompasses uncharged nitric oxide (NO.)and charged nitrogen monoxide species, preferably charged nitrogenmonoxide species, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO−).The reactive form of nitric oxide can be provided by gaseous nitricoxide. The nitrogen monoxide releasing, delivering or transferringcompounds have the structure F-NO, wherein F is a nitrogen monoxidereleasing, delivering or transferring moiety, and include any and allsuch compounds which provide nitrogen monoxide to its intended site ofaction in a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamide (FK-409),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamines, N-((2Z,3E)-4-ethyl-2-(hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3-pyridinecarboxamide(FR 146801), nitrosoamines, furoxans as well as substrates for theendogenous enzymes which synthesize nitric oxide. NONOates include, butare not limited to,(Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino))diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate(“PAPA/NO”),(Z)-1-(N-(3-aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino)diazen-1-ium-1,2-diolate (spermine NONOate or “SPER/NO”) andsodium(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamineNONOate or “DEA/NO”) and derivatives thereof. NONOates are alsodescribed in U.S. Pat. Nos. 6,232,336, 5,910,316 and 5,650,447, thedisclosures of which are incorporated herein by reference in theirentirety. The “NO adducts” can be mono-nitrosylated, poly-nitrosylated,mono-nitrosated and/or poly-nitrosated at a variety of naturallysusceptible or artificially provided binding sites for biologicallyactive forms of nitrogen monoxide.

[1117] One group of NO adducts is the S-nitrosothiols, which arecompounds that include at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

[1118] Another embodiment of the invention is S-nitroso amino acidswhere the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

[1119] Suitable S-nitrosylated proteins include thiol-containingproteins (where the NO group is attached to one or more sulfur groups onan amino acid or amino acid derivative thereof) from various functionalclasses including enzymes, such as tissue-type plasminogen activator(TPA) and cathepsin B; transport proteins, such as lipoproteins; hemeproteins, such as hemoglobin and serum albumin; and biologicallyprotective proteins, such as immunoglobulins, antibodies and cytokines.Such nitrosylated proteins are described in WO 93/09806, the disclosureof which is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

[1120] Other examples of suitable S-nitrosothiols include:

[1121] (i) HS(C(R_(e))(R_(f)))_(m)SNO;

[1122] (ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); or

[1123] (iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

[1124] wherein m is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or—(C(R_(g))(R_(h)))_(k)-T-Q′ or R_(e) and R_(f) taken together are anoxo, a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, ahydrazone or a bridged cycloalkyl group; Q′ is —NO or —NO₂; and T isindependently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T-Q′)(R_(g))(R_(h)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T-Q′)(R_(g))(R_(h)) or —(N₂O₂—).M⁺; then “-T-Q′” can be ahydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group; and

[1125] R_(g) and R_(h) at each occurrence are independently R_(e);

[1126] In cases where R_(e) and R_(f) are a heterocyclic ring or takentogether R_(e) and R_(f) are a heterocyclic ring, then R_(i) can be asubstituent on any disubstituted nitrogen contained within the radicalwherein R_(i) is as defined herein.

[1127] Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetrafluoroborate inan inert solvent.

[1128] Another group of NO adducts for use in the invention, where theNO adduct is a compound that donates, transfers or releases nitricoxide, include compounds comprising at least one ON—O— or ON—N— group.The compounds that include at least one ON—O— or ON—N— group arepreferably ON—O— or ON—N-polypeptides (the term “polypeptide” includesproteins and polyamino acids that do not possess an ascertainedbiological function, and derivatives thereof); ON—O— or ON—N-amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); ON—O— or ON—N-sugars; ON—O— or —ON—N— modified orunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5-200 nucleotides); ON—O— or ON—N— straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted hydrocarbons; and ON—O—, ON—N— or ON—C-heterocycliccompounds.

[1129] Another group of NO adducts for use in the invention includenitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O—, O₂N—N— or O₂N—S— group.Preferred among these compounds are O₂N—O—, O₂N—N— or O₂N-S-polypeptides(the term “polypeptide” includes proteins and also polyamino acids thatdo not possess an ascertained biological function, and derivativesthereof); O₂N—O—, O₂N—N— or O₂N-S-amino acids (including natural andsynthetic amino acids and their stereoisomers and racemic mixtures);O₂N—O—, O₂N—N— or O₂N—S— sugars; O₂N—O—, O₂N—N— or O₂N—S— modified andunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5-200 nucleotides); O₂N—O—, O₂N—N— or O₂N—S— straight orbranched, saturated or unsaturated, aliphatic or aromatic, substitutedor unsubstituted hydrocarbons; and O₂N—O—, O₂N—N— or O₂N—S— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group include isosorbide dinitrate, isosorbidemononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate,nitroglycerin, pentaerythritoltetranitrate, pentrinitrol,propatylnitrate and organic nitrates with a sulfhydryl-containing aminoacid such as, for example SPM 3672, SPM 5185, SPM 5186 and thosedisclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847and 5,883,122 and in WO 97/46521, WO 00/54756 and in WO 03/013432, thedisclosures of each of which are incorporated by reference herein intheir entirety.

[1130] Another group of NO adducts are N-oxo-N-nitrosoamines thatdonate, transfer or release nitric oxide and are represented by theformula: R^(1″)R^(2″)N—N(O-M⁺)—NO, where R^(1″) and R^(2″) are eachindependently a polypeptide, an amino acid, a sugar, a modified orunmodified oligonucleotide, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbon, or a heterocyclic group, and where M⁺ is an organic orinorganic cation, such as, for example, an alkyl substituted ammoniumcation or a Group I metal cation.

[1131] The invention is also directed to compounds that stimulateendogenous NO or elevate levels of endogenous endothelium-derivedrelaxing factor (EDRF) in vivo or are substrates for nitric oxidesynthase. Such compounds include, for example, L-arginine,L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, omithine,glutamine, lysine, polypeptides comprising at least one of these aminoacids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and/orphysiologically acceptable salts thereof, including, for example,pyruvate, pyruvate precursors, α-keto acids having four or more carbonatoms, precursors of α-keto acids having four or more carbon atoms (asdisclosed in WO 03/017996, the disclosure of which is incorporatedherein in its entirety), and the substrates for nitric oxide synthase,cytokines, adenosin, bradykinin, calreticulin, bisacodyl, andphenolphthalein. EDRF is a vascular relaxing factor secreted by theendothelium, and has been identified as nitric oxide (NO) or a closelyrelated derivative thereof (Palmer et al, Nature, 327:524-526 (1987);Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).

[1132] The invention is also based on the discovery that compounds andcompositions of the invention may be used in conjunction with othertherapeutic agents for co-therapies, partially or completely, in placeof other conventional antiinflammatory compounds, such as, for example,together with steroids, NSA/Ds, 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H₂ receptorantagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opiods, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof.

[1133] Leukotriene A₄ (LTA₄) hydrolase inhibitors refer to compoundsthat selectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of lessthan about 10 μM, and preferably with an IC₅₀ of less than about 1 μM.Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acidbenzyl ester,N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine,7-(4-(4-ureidobenzyl)phenyl) heptanoic acid and 3(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, andmixtures of two or more thereof.

[1134] Suitable LTB₄ receptor antagonists include, but are not limitedto, ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270;CGS-25019C; ETH-615; MAFP; TMK-688; T-0757; LY 213024, LY 210073, LY223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111;ONO-LB457, ONO-4057, and ONO-LB-448, S-2474, calcitrol; PF 10042; Pfizer105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228;SB-201146 and SB-209247; SKF-104493; SM 15178; TMK-688; BPC 15, andmixtures of two or more thereof. The preferred LTB₄ receptor antagonistsare calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111,ONO-4057 and TMK-688, and mixtures of two or more thereof.

[1135] Suitable 5-LO inhibitors include, but are not limited to,A-76745, 78773 and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322;ML-3000; PF-5901; R-840; rilopirox, flobufen, linasolast, lonapolene,masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin,rilopirox, flezelastine hydrochloride, enazadrem phosphate, andbunaprolast, and mixtures of two or more thereof. Suitable 5-LOinhibitors are also described more fully in WO 97/29776, the disclosureof which is incorporated herein by reference in its entirety

[1136] Suitable 5-HT agonists, include, but are not limited to,rizatriptan, sumatriptan, naratriptan, zoimitroptan, eieptriptan,aimotriptan, ergot alkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS31416. Suitable 5-HT agonists are described more fully in WO 0025779,and in WO 00/48583. 5-HT agonists refers to a compound that is anagonist to any 5-HT receptor, including but not limited to, 5-HT₁agonists, 5-HT_(1B) agonists and 5-HT_(1D) agonists, and the like.

[1137] Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, 13^(th) Edition.

[1138] Suitable HMG CoA inhibitors, include, but are not limited to,reductase and synthase inhibitors, such as, for example, squalenesynthetase inhibitors, benzodiazepine squalene synthase inhibitors,squalene epoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like. Suitable HMG CoAinhibitors include simvastatin, pravastatin, lovastatin, mevastatin,fluvastatin, atorvastatin, cerivastatin, and the like, and are describedmore fully in U.S. Pat. No. 6,245,797 and WO 99/20110, the disclosuresof which are incorporated herein by reference in their entirety.

[1139] Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen, indomethacin,including but not limited to prodrugs thereof, and the like. SuitableNSAIDs are described more fully in the literature, such as in Goodmanand Gilman, The Pharmacological Basis of Therapeutics (9th Edition),McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, 13^(th)Edition; and in U.S. Pat. Nos. 6,057,347 and 6,297,260 assigned toNitroMed Inc., the disclosures of which are incorporated herein byreference in their entirety.

[1140] Suitable H₂ receptor anatgonists, include, but are not limitedto, cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM,13^(th) Edition; and in WO 00/28988 assigned to NitroMed Inc., thedisclosures of which are incorporated herein by reference in theirentirety.

[1141] Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described in U.S. Pat. No. 6,025,353 and WO 00/38730, the 25disclosures of which are incorporated herein by reference in theirentirety.

[1142] Suitable antiplatelet agents, include but are not limited to,aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIareceptor antagonists, and the like. Suitable antineoplastic agents arealso described in WO 99/45913, the disclosure of which is incorporatedherein by reference in its entirety. In a preferred embodiment of theinvention, the antiplatelet agent is aspirin, more preferably, low-doseaspirin (i.e. 75 mg-100 mg/day).

[1143] Suitable thrombin inhibitors, include but are not limited to,N′-((1-(aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-prolineamide),3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone,3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone,and the like. Suitable thrombin inhibitors are also described in WO00/18352, the disclosure of which is incorporated herein by reference inits entirety.

[1144] Suitable thromboxane inhibitors, include but are not limited tothromboxane synthase inhibitors, thromboxane receptor antagonists, andthe like. Suitable thromboxane inhibitors, are also described in WO01/87343, the disclosure of which is incorporated herein by reference inits entirety.

[1145] Suitable decongestants include, but are not limited to,phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,ephinephrine, naphazoline, xylometazoline, propylhexedrine,levo-desoxyephedrine, and the like.

[1146] Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

[1147] Suitable proton pump inhibitors, include, but are not limited to,omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, andthe like. Suitable proton pump inhibitors are described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; theMerck Index on CD-ROM, 13^(th) Edition; and in WO 00/50037 assigned toNitroMed Inc., the disclosures of which are incorporated herein byreference in their entirety.

[1148] The compounds and compositions of the invention, may also be usedin combination therapies with opioids and other analgesics, including,but not limited to, narcotic analgesics, Mu receptor antagonists, Kappareceptor antagonists, non-narcotic (i.e. non-addictive) analgesics,monoamine uptake inhibitors, adenosine regulating agents, cannabinoidderivatives, neurokinin 1 receptor antagonists, Substance P antagonists,neurokinin-1 receptor antagonists, sodium channel blockers,N-methyl-D-aspartate receptor antagonists, and mixtures of two or morethereof. Preferred combination therapies would be with morphine,meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine,meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608,E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((−) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixturesof two or more thereof.

[1149] The compounds and compositions of the invention can also be usedin combination with inducible nitric oxide synthase (iNOS) inhibitors.Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of eachof which are incorporated by reference herein in their entirety.

[1150] The invention is also based on the discovery that theadministration of a therapeutically effective amount of the compoundsand compositions described herein is effective for treatinginflammation, pain (both chronic and acute), and fever, such as, forexample, analgesic in the treatment of pain, including, but not limitedto headaches, migraines, postoperative pain, dental pain, muscular pain,and pain resulting from cancer; as an antipyretic for the treatment offever, including but not limited to, rheumatic fever, symptomsassociated with influenza or other viral infections, common cold, lowback and neck pain, dysmenorrhea, headache, toothache, sprains, strains,myositis, neuralgia, synovitis; arthritis, including but not limited torheumatoid arthritis, degenerative joint disease (osteoarthritis),spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis. For example, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated, and at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Inyet another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and, atleast one therapeutic agent, including but not limited to, steroids,nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO)inhibitors, leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄(LTA₄) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

[1151] Another embodiment of the invention provides methods for treatinggastrointestinal disorders and/or improving the gastrointestinalproperties of the COX-2 selective inhibitor by administering to thepatient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. Such gastrointestinaldisorders refer to any disease or disorder of the upper gastrointestinaltract (e.g., esophagus, the stomach, the duodenum, jejunum) including,for example, inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome, ulcerative colitis, peptic ulcers, stressulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated In another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and, at least one therapeutic agent, including butnot limited to, including but not limited to, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

[1152] Yet another embodiment of the invention provides methods forfacilitating wound healing (such as, for example, ulcer healing, bonehealing including osteoporosis) by administering to the patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Wound refers to, and includes, any lesionthat is characterized by loss of tissue, and, includes, but is notlimited to, ulcers, cuts, bums, bone fractures, orthopedic procedure,wound infliction, and the like. Ulcers refers to lesions of the uppergastrointestinal tract lining that are characterized by loss of tissue,and, include, but are not limited to, gastric ulcers, duodenal ulcers,gastritis, and the like. For example, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated, and at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Inyet another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and, atleast one therapeutic agent, and, optionally, at least one nitric oxidedonor. The compounds can be administered separately or in the form of acomposition.

[1153] Another embodiment of the invention provides methods to decreaseor reverse renal and/or other toxicities (such as, for example, kidneytoxicity, respiratory toxicity) by administering to a patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. For example, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylatedIn another embodiment, the patient can be administered a therapeuticallyeffective amount of at least one COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, and at least one nitric oxidedonor. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one therapeutic agent, and, optionally, at least one nitric oxidedonor. The compounds can be administered separately or in the form of acomposition.

[1154] Another embodiment of the invention provides methods to treat orprevent disorders resulting from elevated levels of COX-2 byadministering to a patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Forexample, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated. In another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and at least one therapeutic agent, including butnot limited to, steroids, a nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

[1155] Disorders resulting from elevated levels of COX-2 (e.g., COX-2mediated disorders) include, but are not limited to, for example,angiogenisis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis; skin-related conditions, such as, forexample, psoriasis, eczema, surface wounds, burns and dermatitis;post-operative inflammation including from ophthalmic surgery, such as,for example, cataract surgery and refractive surgery, and the like;treatment of neoplasia, such as, for example, brain cancer, bone cancer,epithelial cell-derived neoplasia (epithelial carcinoma), such as, forexample, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer,such as, for example, lip cancer, mouth cancer, esophageal cancer, smallbowel cancer and stomach cancer, colon cancer, liver cancer, bladdercancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer,breast cancer and skin cancer, such as squamus cell and basal cellcancers, prostate cancer, renal cell carcinoma, and other known cancersthat effect epithelial cells throughout the body, benign and canceroustumors, growths, polyps, adenomatous polyps, including, but not limitedto, familial adenomatous polyposis, fibrosis resulting from radiationtherapy, and the like; treatment of inflammatory processes in diseases,such as, for example, vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury, myocardial ischemia, and the like; treatment ofophthalmic diseases and disorders, such as, for example, retinitis,retinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, glaucoma, inflammation of the eye and elevation of intraocularpressure and the like; treatment of pulmonary inflammation, such as, forexample, those associated with viral infections and cystic fibrosis, andthe like; treatment of central nervous system disorders, such as, forexample, cortical dementia including Alzheimer's disease, vasculardementia, multi-infarct dementia, pre-senile dementia, alcoholicdementia, senile dementia, and central nervous system damage resultingfrom stroke, ischemia and trauma, and the like; treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis; treatment of inflammations and/or microbial infectionsincluding, for example, inflammations and/or infections of the eyes,ears, nose, throat, and/or skin; treatment and/or prevention ofcardiovascular disorders, such as, for example, coronary artery disease,aneurysm, arteriosclerosis, atherosclerosis, including, but not limitedto, cardiac transplant atherosclerosis, myocardial infarction,hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosis,thromboembolism, thrombotic occlusion and reclusion, restenosis, angina,unstable angina, shock, heart failure, coronary plaque inflammation,bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation, viral induced inflammation, inflammation associated withsurgical procedures, such as, for example, vascular grafting, coronaryartery bypass surgery, revascularization procedures, such as, forexample, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;treatment and/or prevention of urinary and/or urological disorders, suchas, for example, incontinence and the like; treatment and/or preventionof endothelial dysfunctions, such as, for example, diseases accompanyingthese dysfunctions, endothelial damage from hypercholesterolemia,endothelial damage from hypoxia, endothelial damage from mechanical andchemical noxae, especially during and after drug, and mechanicalreopening of stenosed vessels, for example, following percutaneoustransluminal angiography (PTA) and percuntaneous transluminal coronaryangiography (PTCA), endothelial damage in postinfarction phase,endothelium-mediated reocculusion following bypass surgery, blood supplydisturbances in peripheral arteries, as well as, cardiovasculardiseases, and the like; methods for treating and/or preventing tissuedeterioration, such as, for example, for organ transplants, and thelike; disorders treated by the inhibition and/or prevention ofactivation, adhesion and infiltration of neutrophils at the site ofinflammation; and disorders treated by the inhibition and/or preventionof platelet aggregation. The compounds and compositions of the inventioncan also be used as a pre-anesthetic medication in emergency operationsto reduce the danger of aspiration of acidic gastric contents.

[1156] Another embodiment of the invention provides methods forimproving the cardiovascular profile of COX-2 selective inhibitors byadministering to a patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 selectiveinhibitor of the invention. In another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one nitric oxide donor. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, at least one of 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, and, optionally, at least one nitric oxidedonor. The compounds can be administered separately or in the form of acomposition.

[1157] When administered separately, the COX-2 selective inhibitor, thatis optionally nitrosated and/or nitrosylated, can be administered aboutthe same time as part of the overall treatment regimen, i.e., as acombination therapy. “About the same time” includes administering theCOX-2 selective inhibitor, that is optionally nitrosated and/ornitrosylated, simultaneously, sequentially, at the same time, atdifferent times on the same day, or on different days, as long as theyare administered as part of an overall treatment regimen, i.e.,combination therapy or a therapeutic cocktail.

[1158] When administered in vivo, the compounds and compositions of theinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the invention are administered as a combination ofat least one COX-2 selective inhibitor and/or at least one nitrosatedand/or nitrosylated COX-2 selective inhibitor and/or at least one nitricoxide donor and/or therapeutic agent, they can also be used incombination with one or more additional compounds which are known to beeffective against the specific disease state targeted for treatment. Thenitric oxide donors, therapeutic agents and/or other additionalcompounds can be administered simultaneously with, subsequently to, orprior to administration of the COX-2 selective inhibitor and/ornitrosated and/or nitrosylated COX-2 selective inhibitor.

[1159] The compounds and compositions of the invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.,by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. Parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

[1160] Transdermal compound administration, which is known to oneskilled in the art, involves the delivery of pharmaceutical compoundsvia percutaneous passage of the compound into the systemic circulationof the patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

[1161] Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of theinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

[1162] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions can also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[1163] Suppositories for vaginal or rectal administration of thecompounds and compositions of the invention, such as for treatingpediatric fever and the like, can be prepared by mixing the compounds orcompositions with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at room temperature butliquid at rectal temperature, such that they will melt in the rectum andrelease the drug.

[1164] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

[1165] The compositions of this invention can further includeconventional excipients, i.e., pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral application whichdo not deleteriously react with the active compounds. Suitablepharmaceutically acceptable carriers include, for example, water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, surfactants, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

[1166] The composition, if desired, can also contain minor amounts ofwetting agents, emulsifying agents and/or pH buffering agents. Thecomposition can be a liquid solution, suspension, emulsion, tablet,pill, capsule, sustained release formulation, or powder. The compositioncan be formulated as a suppository, with traditional binders andcarriers such as triglycerides. Oral formulations can include standardcarriers such as pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,and the like.

[1167] Various delivery systems are known and can be used to administerthe compounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered as asingle unit or in a sustained release form.

[1168] The bioavailability of the compositions can be enhanced bymicronization of the formulations using conventional techniques such asgrinding, milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

[1169] The preferred methods of administration of the COX-2 selectiveinhibitors and compositions for the treatment of gastrointestinaldisorders are orally, bucally or by inhalation. The preferred methods ofadministration for the treatment of inflammation and microbialinfections are orally, bucally, topically, transdermally or byinhalation.

[1170] The compounds and compositions of the invention can be formulatedas pharmaceutically acceptable salt forms. Pharmaceutically acceptablesalts include, for example, alkali metal salts and addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesuifonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitablepharmaceutically-acceptable base addition salts include, but are notlimited to, metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromprimary, secondary and tertiary amines, cyclic amines,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine and thelike. All of these salts may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

[1171] While individual needs may vary, determination of optimal rangesfor effective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

[1172] The amount of a given COX-2 selective inhibitor of the inventionthat will be effective in the treatment of a particular disorder orcondition will depend on the nature of the disorder or condition, andcan be determined by standard clinical techniques, including referenceto Goodman and Gilman, supra; The Physician's Desk Reference, MedicalEconomics Company, Inc., Oradell, N.J., 1995; and Drug Facts andComparisons, Inc., St. Louis, Mo., 1993. The precise dose to be used inthe formulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided by thephysician and the patient's circumstances.

[1173] The amount of nitric oxide donor in a pharmaceutical compositioncan be in amounts of about 0.1 to about 10 times the molar equivalent ofthe COX-2 selective inhibitor. The usual daily doses of the COX-2selective inhibitors are about 0.001 mg to about 140 mg/kg of bodyweight per day, preferably 0.005 mg to 30 mg/kg per day, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, inflammations may be effectively treated by the administrationof from about 0.01 mg to 50 mg of the compound per kilogram of bodyweight per day, or alternatively about 0.5 mg to about 3.5 g per patientper day. The compounds may be administered on a regimen of up to 6 timesper day, preferably 1 to 4 times per day, and most preferably once perday. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems and are in the sameranges or less than as described for the commercially availablecompounds in the Physician's Desk Reference, supra.

[1174] The invention also provides pharmaceutical kits comprising one ormore containers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the invention,including, at least, one or more of the novel COX-2 selectiveinhibitors, that is optionally nitrosated and/or nitrosylated, and oneor more of the NO donors described herein. Associated with such kits canbe additional therapeutic agents or compositions (e.g., steroids,NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists and leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMG-CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like), devices for administering the compositions,and notices in the form prescribed by a governmental agency regulatingthe manufacture, use or sale of pharmaceuticals or biological productswhich reflects approval by the agency of manufacture, use or sale forhumans.

EXAMPLES

[1175] The following non-limiting examples further describe and enableone of ordinary skill in the art to make and use the invention. In eachof the examples, flash chromatography was performed on 40 micron silicagel (Baker).

Example 11-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)Benzene

[1176] 1a. N-((1Z)-1-Aza-2-cyclohexylvinyl)(tert-butoxy)carboxamide

[1177] Cyclohexane carboxaldehyde (5.0 g, 44.5 mmol) and t-butylcarbazate (5.89 g, 44.5 mmol) in methanol (140 mL) was stirred at roomtemperature for 1 hour. The solvent was evaporated and the resultingsolid dried under vacuo to give a white solid in quantitative yield; mp123-125° C. ¹H NMR (300 MHz, CDCl₃) δ 7.61 (bs, 1H), 7.02 (d, J=5.9 Hz,1H), 2.22-2.39 (m, 1H), 1.60-1.89 (m, 5H), 1.49 (s, 9H), 1.19-1.47 (m,5H); ¹³C NMR (75 MHz, CDCl₃) δ 152.5, 151.5, 81.0, 40.7, 30.4, 28.5,26.0, 25.6; mass spectrum (API-TIS) m/z 227 (MH⁺), 249 (MNa⁺). Anal.calcd for C₁₂H₂₂N₂O₂: C, 63.69; H, 9.80; N, 12.38. Found: C, 63.97; H,9.76; N, 12.26.

[1178] 1b. (tert-Butoxy)-N-((cyclohexylmethyl)amino)carboxamide

[1179] Sodium cyanoborohydride (2.8 g, 44.6 mmol) was added portionwiseto a suspension of the product of Example 1a (10.1 g, 44.6 mmol) in 50%acetic acid (125 mL) at room temperature. The resultant clear solutionwas stirred at room temperature for 2 hours. The reaction mixture wasneutralized with 1N NaOH, extracted with CH₂Cl₂, washed with saturatedNaHCO₃, dried, filtered and evaporated to give the title compound as acolorless oil in quantitative yield. ¹H NMR (300 MHz, CDCl₃) δ 6.90 (bs,1H), 6.15 (bs, 1H), 2.68 (d, J=6.7 Hz, 2H), 2.25-2.50 (m, 1H), 1.60-1.87(m, 5H), 1.46 (s, 9H), 1.12-1.33 (m, 3H), 0.80-1.08 (m, 2H); massspectrum (API-TIS) m/z 129 (MH⁺).

[1180] 1c. Cyclohexylmethylhydrazine Trifluoroacetate

[1181] Trifluoroacetic acid (20 mL) was added dropwise to a solution ofthe product of Example 1b (6.4 g, 28.1 mmol) in CH₂Cl₂ (20 mL). Thereaction mixture was stirred at room temperature for 1 hour. The solventwas evaporated to give the trifluoroacetate salt of the title compoundas a colorless oil in quantitative yield. ¹H NMR (300 MHz, CDCl₃) δ 8.80(bs, 5H), 2.98-3.08 (m, 2H), 1.64-1.92 (m, 6H), 1.12-1.47 (m, 3H),0.90-1.10 (m, 2H); mass spectrum (API-TIS) m/z 129 (MH⁺).

[1182] 1d. Methyl(2Z)-2-hydroxy-4-(4-methylthiophenyl)-4-oxobut-2-enoate

[1183] Dimethyloxalate (26 g, 180.7 mmol) was added to a stirredsuspension of sodium methoxide (9.75 g, 180.7 mmol) in dry toluene (200mL) at 0° C. The white suspension was stirred for 15 minutes at 0° C. Asolution of 4′-(methylthio)acetophenone (15 g, 90.4 mmol) in dry toluene(150 mL) was then added dropwise over 15 minutes giving a yellowsuspension which was stirred for 2 hours at room temperature. The thickyellow suspension was transferred to a 2 liter flask and stirredvigorously with 10% HCl (250 mL) and EtOAc (200 mL) to dissolve all thesolids present. The organic layer was separated and the aqueous layerwas extracted with EtOAc (100 mL). The combined organic extracts werewashed with water (250 mL), dried over Na₂SO₄ and the solvent wasevaporated under reduced pressure to give thick brown oil. The brown oilwas dissolved in CH₂Cl₂ (25 mL) and hexane (125 mL) and left in afreezer at −20° C. for 16 hours to give the title compound (18 g, 79%)as orange color solid; mp 81° C. ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d,J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 6.97 (s, 1H), 3.89 (s, 3H), 2.47(s, 3H); ¹³C NMR (75 MHz, CDCl₃); mass spectrum (API-TIS) m/z 253 (MH⁺).Anal. calcd for C₁₂H₁₂O₄S: C, 57.13; H, 4.79; S, 12.71. Found: C, 56.85;H, 4.76; S, 12.43.

[1184] 1e. Methyl1-(cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazole-3-carboxylate

[1185] A mixture of the product of Example 1d (2 g, 7.9 mmol) and theproduct of Example 1c (3.5 g, 10.3 mmol) in methanol (40 mL) was heatedat 70° C. for 2 hours and cooled to room temperature. The mixture wasmade basic with 5% Na₂CO₃ and extracted with EtOAc which was then washedwith saturated NaHCO₃ and water. The organic extracts were dried overNa₂SO₄ and the solvent was evaporated under reduced pressure to give athick oil, which was purified by chromatography over silica gel elutingwith 1:2 EtOAc:Hex to give the title compound as a pale yellow solid(1.55 g, 57%); mp 92° C. ¹H NMR (300 MHz, CDCl₃) δ 7.15-7.30 (m, 4H),6.76 (s, 1H), 3.99 (d, J=7.4 Hz, 2H), 3.94 (s, 3H), 2.54 (s, 3H),1.82-2.00 (m, 1H), 1.35-1.63 (m, 5H), 0.97-1.18 (m, 3H), 0.67-0.84 (m,2H). ¹³C NMR (75 MHz, CDCl₃) δ 163.1, 145.2, 142.6, 140.2, 129.6, 126.5,126.3, 108.9, 56.4, 52.1, 38.7, 30.5, 26.3, 25.6, 15.4; mass spectrum(API-TIS) m/z 345 (MH⁺). Anal. calcd for C₁₉H₂₄N₂O₂S: C, 66.25; H, 7.02;N, 8.13. Found: C, 66.31; H, 7.20; N, 8.15.

[1186] 1f.(1-(Cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazol-3-yl)methan-1-ol

[1187] Lithium aluminum hydride (2.0 mL of 1M solution in THF, 79.0 mg,2.09 mmol) was added dropwise to a solution of the product of Example 1e(0.72 g, 2.09 mmol) in THF (14 mL) at 0° C. The yellow solution wasstirred at room temperature for 1 hour. Solid Na₂SO₄.10H₂O was addedportionwise to the reaction mixture at 0° C., followed by few drops ofwater and 0.1 N NaOH. The solid was filtered and washed with EtOAc. Thesolvent was evaporated to give the title compound (0.5 g, 76%) as awhite foam. ¹H NMR (300 MHz, CDCl₃) δ 7.13-7.30 (m, 4H), 6.22 (s, 1H),4.70 (s, 2H), 3.88 (d, J=7.3 Hz, 2H), 3.65 (bs, 1H), 2.53 (s, 3H),1.75-1.83 (m, 1H), 1.40-1.68 (m, 5H), 0.92-1.28 (m, 3H), 0.60-0.82 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 151.5, 144.8, 139.5, 129.3, 127.2, 126.1,104.6, 58.0, 55.3, 38.7, 30.3, 26.0, 25.5, 15.1; mass spectrum (API-TIS)m/z 317 (MH⁺), 299 (M−OH).

[1188] 1g.1-(1-(Cyclohexylmethyl)-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1189] The product of Example 1f (0.5 g, 1.58 mmol) was dissolved inMeOH (32 mL). OXONE® (1.94 g, 3.16 mmol) in water (7 mL) was added atroom temperature. The reaction mixture was stirred for 1 hour and theresulting solid was removed by filtration. CH₂Cl₂ was added to thefiltrate, and then the organic layer was washed with saturated NaHCO₃,water, dried over Na₂SO₄, and filtered. The residue after evaporation ofthe solvent was recrystallized from CH₂Cl₂/EtOAc/Hexane to give thetitle compound (0.33 g, 59%) as a white solid; mp 104° C. ¹H NMR (300MHz, CDCl₃) δ 8.04 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), 6.32 (s,1H), 4.74 (d, J=5.8 Hz, 2H), 3.92 (d, J=7.3 Hz, 2H), 3.13 (s, 3H), 1.98(t, J=5.9 Hz, 1H), 1.801.94 (m, 1H), 1.40-1.70 (m, 5H), 0.98-1.25 (m,3H), 0.65-0.82 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 151.8, 143.3, 140.6,136.7, 130.0, 128.0, 105.4, 59.2, 56.0, 44.6, 39.0, 30.7, 26.3, 25.7;mass spectrum (API-TIS) m/z 349 (MH⁺), 331 (M−OH). Anal. Calcd forC₁₈H₂₄N₂O₃S: C, 62.04; H, 6.94; N, 8.04; S, 9.20. Found: C, 61.88; H,6.91; N, 7.84; S, 9.09.

[1190] 1h.1-(1-(Cyclohexylmethyl)-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1191] The product of Example 1g (0.22 g, 0.62 mmol) in CHCl₃ (2.6 mL)was added to a mixture of fuming HNO₃ (130 μL, 0.19 g, 3.1 mmol) andAc₂O (0.47 mL, 0.5 g, 4.96 mmol) at −10° C. and stirred at −10° C. for20 minutes. The reaction mixture was quenched with ice-cold water andextracted with CH₂Cl₂. The extracts were washed with ice-cold saturatedNaHCO₃, water, dried over Na₂SO₄, filtered and the solvent evaporatedunder reduced pressure. The residue obtained was recrystallized fromCH₂Cl₂/EtOAc/Hex to give the title compound as a white solid (0.17 g,70%); mp 98-99° C. ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d, J=8.3 Hz, 2H),7.58 (d, J=8.3 Hz, 2H), 6.41 (s, 1H), 5.50 (s, 2H), 3.93 (d, J=7.3 Hz,2H), 3.13 (s, 3H), 1.80-1.97 (m, 1H), 1.40-1.68 (m, 5H), 1.00-1.28 (m,3H), 0.67-0.82 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 138.31, 138.27, 135.6,130.7, 124.7, 122.7, 102.2, 63.2, 50.9, 39.2, 33.6, 25.3, 20.9, 20.3;mass spectrum (API-TIS) m/z 394 (MH⁺). Anal. calcd for C₁₈H₂₃N₃O₅S: C,54.95; H, 5.89; N, 10.68; S, 8.15. Found: C, 54.96; H, 5.94; N, 10.49;S, 8.31.

Example 21-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)Benzene

[1192] 2a. Methyl(2Z)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-4-oxobut-2-enoate

[1193] Sodium methoxide was prepared by dissolving Na (6.9 g, 30 mmol)in MeOH (400 mL). The solution was cooled to 0° C. Dimethyl oxalate (33g, 280 mmol) was added followed by1-(4-(methylsulfonyl)phenyl)ethan-1-one (28 g, 140 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 18hours. The MeOH was evaporated and the residue triturated with 1N HCl(600 mL). The solid was collected on filter paper, washed with H₂O(2×250), and dried in vacuo. This gave the title compound (39 g, 100%)as a tan solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.17 (d, J=6.9 Hz, 2H), 8.09(d, J=6.9 Hz, 2H), 7.10 (s, 1H), 3.97 (s, 3H), 3.10 (s, 3H).

[1194] 2b. Methyl1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazole-3-carboxylate

[1195] The product of Example 1c (8 mL, 23 mmol) and the product ofExample 2a (4.5 g, 16 mmol) were added to MeOH and heated at reflux for3 hours. The reaction mixture was cooled to room temperature and dilutedwith H₂O (150 mL). The aqueous MeOH solution was extracted with CH₂Cl₂(3×50). The combined organic extracts were washed with 1N Na₂CO₃ (2×50)and 1N HCl (1×50), dried over Na₂SO₄, concentrated. The residue wascrystallized from MeOH (15 mL) to give the title compound (3.5 g, 58%)as a white solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.06 (d, J=8.4 Hz, 2H), 7.60(d, J=8.4 Hz, 2H), 6.87 (s, 1H), 4.02 (d, J=7.5 Hz, 2H), 3.96 (s, 3H),3.13 (s, 3H), 0.73-1.94 (mult, 11H).

[1196] 2c.4-(1-(Cyclohexylmethyl)-3-(hydroxymethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

[1197] A flask was charged with lithium aluminum hydride (125 mg, 3.3mmol) in THF (5 mL) and cooled to 0° C. The product of Example 2b (750mg, 2 mmol) in THF (5 mL) was added dropwise. The resulting mixture wasstirred at 0° C. for 15 minutes then warmed to room temperature withstirring for 1.5 hours. The excess lithium aluminum hydride wasdestroyed by adding sequentially H₂O (150 μL), 15% NaOH (150 μL), H₂O(450 μL). The precipitate that formed was removed by filtration throughCelite, the filter cake was washed with EtOAc (2×10). The combinedfiltrates were dried over Na₂SO₄ and concentrated to give the titlecompound (790 mg, 100%) as a white solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.04(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 6.33 (s, 1H), 4.73 (d, J=5.1Hz, 2H), 3.91 (d, J=7.2 Hz, 2H), 3.13 (s, 3H), 0.73-2.09 (mult, 11H).

[1198] 2d.4-(3-(Bromomethyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

[1199] The product of Example 2c (790 mg, 2 mmol) was dissolved inCH₂Cl₂ (5 ML). Phosphorous tribromide (100 μL, 1 mmol) was added and themixture was stirred at room temperature for 18 hours. The reactionmixture was transferred to a separation funnel with CH₂Cl₂ (40 mL) andwashed with H₂O (1×10) and dried over Na₂SO₄. Evaporation of the solventgave a residue that was filtered through silica gel eluting withHex:EtOAc 1:1 to give the title compound (440 mg, 53%) as a white solid,mp 141-143° C. ¹H-NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.2 Hz, 2H), 7.59(d, J=8.2 Hz, 2H), 6.39 (s, 1H), 4.53 (s, 2H), 3.91 (d, J=7.3 Hz, 2H),3.13 (s, 3H), 0.73-1.88 (mult, 1H); mass spectrum (API-TIS) m/z 411(MH⁺). Anal calcd for C₁₈H₂₃BrN₂O₂S: C, 52.56; H, 5.64; N, 6.81. FoundC, 52.47; H, 5.67; N, 6.65.

[1200] 2e.4-(1-(Cyclohexylmethyl)-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-1(methylsulfonyl)benzene

[1201] To a slurry of 95% NaH (75 mg, 3 mmol) in THF (5 mL) was added2-benzyloxyethanol (275 μL, 2 mmol). The mixture was stirred at roomtemperature for 15 minutes by which time effervescence had ceased. Theproduct of Example 2d (410 mg, 1 mmol) in THF (2 mL) was added and thereaction mixture was stirred at room temperature for 18 hours. ExcessNaH was quenched with saturated NH₄Cl (20 mL). The aqueous THF wasextracted with EtOAc (3×20). The combined extracts were washed with H₂O,brine, dried over Na₂SO₄, and concentrated. The residue was taken up inEtOAc (30 mL), 10% Pd/C (300 mg) was added and the mixture was shakenunder 50 psi of hydrogen for 18 hours. The reaction mixture was filteredthrough Celite and the filter cake was washed with EtOAc (2×25). Thecombined filtrate was washed with H₂O (2×25) and brine (1×25), driedover Na₂SO₄, and concentrated. Chromatography of the residue on silicagel eluting with Hex:EtOAc 1:2 gave the title compound (200 mg, 51%) asa white solid, mp 73-75° C. ¹H-NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.2 Hz,2H), 7.58 (d, J=8.2 Hz, 2H), 6.33 (s, 1H4.64 (t, J=4.1 Hz, 2H), 4.62 (s,2H), 3.92 (d, J=7.3 Hz, 2H), 3.77 (br mult, 2H), 3.67-3.69 (Mult 2H),3.12 (s, 3H), 0.73-1.91 (mult, 10H); mass spectrum (API-TIS) m/z 393(MH⁺). Anal calcd for C₂₀H₂₈N₂O₄S: C, 61.20; H, 7.19; N, 7.14. Found C,60.97; H, 6.99; N, 7.02.

[1202] 2f.4-(1-(Cyclohexylmethyl)-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

[1203] Fuming 90% HNO₃ (0.5 mL, 12 mmol) was cooled to 0° C. The productof Example 2e (200 mg, 0.5 mmol) was added and allowed to stir at 0° C.for 45 minutes. The reaction mixture was poured in to 0.5 N Na₂CO₃ (20mL). The aqueous mixture was extracted with EtOAc (2×15). The combinedextracts were washed with brine, dried over Na₂SO₄, and concentrated.The residue was triturated with Hex:EtOAc 2:1 (2 ml). The solid wasisolated by filtration to give the title compound (100 mg, 50%) as apale yellow solid. mp 98-100° C. ¹H-NMR (300 MHz, CDCl₃) δ 8.04 (d,J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 6.36 (s, 1H), 4.64 (t, J=4.1 Hz,2H), 4.60 (s, 2H), 3.92 (d, J=7.3 Hz, 2H), 3.83 (t, J=4.4 Hz, 2H), 3.13(s, 3H), 0.70-1.87 (mult, 11H); mass spectrum (API-TIS) m/z 348 (MH⁺).Anal calcd for C₂₀H₂₇N₃O₆S: C, 54.91; H, 6.22; N, 9.60. Found C, 54.17;H, 6.38; N, 9.24.

Example 34-(Methylsulfonyl)-1-(3-((nitrooxy)methyl)-1-benzylpyrazol-5-yl)benzene

[1204] 3a. Methyl 5-(4-(methylthiophenyl)-1-benzylpyrazole-3-carboxylate

[1205] A mixture of the product Example 1d (2 g, 7.9 mmol) andbenzylhydrazine hydrochloride (1.64 g, 10.3 mmol) in methanol (40 mL)and trifluoroacetic acid (0.5 mL) was heated at 70° C. for 2 hours andcooled to room temperature. The mixture was made basic with 5% Na₂CO₃and extracted with EtOAc which was then washed with saturated NaHCO₃ andwater. The organic extracts were dried over Na₂SO₄ and the solvent wasevaporated. The residue was recrystallized from CH₂Cl₂/EtOAc/Hex to givethe title compound as a white solid (1.88 g, 70%); mp 94-96° C. ¹H NMR(300 MHz, CDCl₃) δ 7.12-7.30 (m, 7H), 7.00-7.08 (m, 2H), 6.87 (s, 1H),5.41 (s, 2H), 3.95 (s, 3H), 2.50 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ163.0, 145.2, 143.1, 140.6, 136.7, 129.4, 128.8, 127.9, 126.9, 126.3,126.0, 109.4, 54.2, 52.2, 15.4; mass spectrum (API-TIS) m/z 339 (MH⁺),307 (M−OCH₃); Anal. Calcd for C₁₉H₁₈N₂O₂S: C, 67.43; H, 5.36; N, 8.28;S, 9.47. Found: C, 67.56; H, 5.39; N, 8.29; S, 9.39.

[1206] 3b. (5-(4-(Methylthiophenyl)-1-benzylpyrazol-3-yl)methan-1-ol

[1207] The title compound was prepared as a white foam in quantitativeyield from the product of Example 3a by following the procedure forExample 1f. ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.28 (m, 7H), 7.02-7.04 (m,2H), 6.32 (s, 1H), 5.28 (s, 2H), 4.70 (s, 2H), 2.49 (s, 3H). ¹³C NMR (75MHz, CDCl₃) δ 152.1, 144.9, 139.9, 137.6, 129.3, 128.8, 127.7, 127.1,126.8, 126.4, 104.9, 59.1, 53.2, 15.5; mass spectrum (API-TIS) m/z 311(MH⁺), 293 (M−OH).

[1208] 3c.1-(3-(Hydroxymethyl)-1-benzylpyrazol-5-yl)-4-(methylsulfonyl)benzene

[1209] The title compound was prepared as a white solid (0.55 g, 66%)from the product of Example 3b by following the procedure for Example1g; mp 155° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.4 Hz, 2H), 7.51(dd, J=1.7 and 6.9 Hz, 2H), 7.27-7.30 (m, 3H), 7.02-7.05 (m, 2H), 6.45(s, 1H), 5.33 (s, 2H), 4.76 (d, J=5.8 Hz, 2H), 3.08 (s, 3H), 2.26 (t,J=5.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 152.4, 143.2, 140.6, 137.0,136.0, 129.7, 129.0, 127.9, 126.6, 106.0, 59.0, 53.6, 44.6. Massspectrum (API-TIS) m/z 343 (MH⁺). Anal. Calcd for C₁₈H₁₈N₂O₃S: C, 63.14;H, 5.30; N, 8.18; S, 9.36. Found: C, 62.97; H, 5.23; N, 8.03; S, 9.16.

[1210] 3d.4-(Methylsulfonyl)-1-(3-((nitrooxyl)methyl)-1-benzylpyrazol-5-yl)benzene

[1211] The title compound was prepared as a white solid (0.22 g, 57%)from the product of Example 3c by following the procedure for Example1h; mp 93-94° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.97 (dd, J=1.6 and 6.8 Hz,2H), 7.49 (dd, J=1.7 and 6.7 Hz, 2H), 7.26-7.33 (m, 3H), 7.01-7.03 (m,2H), 6.53 (s, 1H), 5.54 (s, 2H), 5.35 (s, 2H), 3.08 (s, 3H). ¹³C NMR (75MHz, CDCl₃) δ 144.3, 143.6, 141.1, 136.6, 135.4, 129.8, 129.0, 128.2,128.0, 126.7, 108.1, 68.4, 53.9, 44.5; mass spectrum (API-TIS) m/z 388(MH⁺). Anal. Calcd for C₁₈H₁₇N₃O₅S: C, 55.81; H, 4.42; N, 10.85; S,8.28. Found: C, 55.57; H, 4.37; N, 10.78; S, 8.50.

Example 41-(3-((1E)-3-(nitrooxy)prop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1212] 4a.1-(Cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazole-3-carbaldehyde

[1213] To a stirred solution of oxalyl chloride (0.60 mL, 0.87 g, 6.8mmol) in CH₂Cl₂ (2.3 mL) at −78° C. under nitrogen was added DMSO (0.97mL, 1.06 g, 13.7 mmol) in CH₂Cl₂ (1.8 mL) dropwise over a period of 20min. To this solution the product of Example 1f (1.73 g, 5.47 mmol) inCH₂Cl₂ (10 mL) was added dropwise over a period of 40 minutes at −78° C.The mixture was stirred at −78° C. for 1.5 hours. Triethylamine (3.8 mL,2.77 g, 27.3 mmol) in CH₂Cl₂ (2.3 mL) was then added dropwise over aperiod of 45 minutes at −78° C. The resultant mixture was stirred at 0°C. for 20 minutes. To this mixture, water (2 mL) was added dropwisefollowed by CH₂Cl₂ (50 mL). The organic layer was separated and theaqueous layer was extracted with CH₂Cl₂. The combined organic extractswere washed with 5% HCl, dried over Na₂SO₄ and filtered. The residueafter evaporation of the solvent was chromatographed on silica geleluting with 1:9 EtOAc/Hexane to give the title compound (1.6 g, 93%) asa clear oil. ¹H NMR (300 MHz, CDCl₃) δ 9.99 (s, 1H), 7.22-7.37 (m, 4H),6.75 (s, 1H), 4.01 (d, J=7.4 Hz, 2H), 2.54 (s, 3H), 1.83-2.00 (m, 1H),1.42-1.69 (m, 5H), 1.00-1.25 (m, 3H), 0.73-0.89 (m, 2H). ¹³C NMR (75MHz, CDCl₃) δ 181.7, 145.3, 145.2, 140.6, 135.2, 124.2, 120.9, 100.4,51.2, 33.5, 25.2, 20.9, 20.3, 10.1; mass spectrum (API-TIS) m/z 315(MH⁺); Anal. Calcd for C₁₈H₂₂N₂OS: C, 68.75; H, 7.05; N, 8.91. Found: C,68.48; H, 6.82; N, 8.88.

[1214] 4b. Methyl(2E)-3-(1-(cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazol-3-yl)prop-2-enoate

[1215] n-Butyl lithium (2.5 M solution in hexane, 1.65 mL, 0.27 g, 4.14mmol) was added dropwise to a solution of trimethylphosphonoacetate(0.70 g, 3.82 mmol) in THF (7 mL) at −78° C. The resultant solution wasstirred at −78° C. for 1 hour. To this solution the product from Example4a (1.0 g, 3.18 mmol) in THF (7 mL) was added dropwise. The reactionmixture was stirred at −78° C. for 1 hour. The reaction mixture wasgradually allowed to warm to room temperature and stirred for 24 hours.Water was added and extracted with EtOAc, which was then washed withwater, dried over Na₂SO₄ and filtered. The residue obtained afterevaporation of the solvent was purified by chromatography over silicagel eluting with 1:9 to 2:8 EtOAc:Hexane to give the pure E-isomer (1.04g, 88%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=16.0Hz, 1H), 7.20-7.34 (m, 4H), 6.45 (s, 1H), 6.40 (d, J=16.2 Hz, 1H), 3.92(d, J=7.3 Hz, 2H), 3.79 (s, 3H), 2.53 (s, 3H), 1.80-1.98 (m, 1H),1.37-1.70 (m, 5H), 0.92-1.22 (m, 3H), 0.62-0.82 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ 167.6, 147.2, 145.4, 140.0, 137.3, 129.6, 127.0, 126.3,118.5, 105.1, 56.0, 51.7, 38.9, 30.6, 26.3, 25.7, 15.5; mass spectrum(API-TIS) m/z 371 (MH⁺); Anal. Calcd for C₂₁H₂₆N₂O₂S: C, 68.08; H, 7.07;N, 7.56. Found: C, 67.77; H, 6.76; N, 7.39.

[1216] 4c.(2E)-3-(1-(Cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazol-3-yl)prop-2-en-1-ol

[1217] Lithium aluminum hydride (2.0 mL of 1M solution in THF, 75.9 mg,2.0 mmol) was added dropwise to a solution of the product of Example 4b(0.74 g, 2.0 mmol) in THF (11 mL) at 0° C. The yellow solution wasstirred for 30 min at 0° C. and at room temperature for 30 min. SolidNa₂SO₄.10H₂O was added portionwise to the reaction mixture at 0° C.,followed by few drops of water and 0.1 N NaOH. The solid was filteredand washed with EtOAc. The solvent was evaporated and the product waspurified by column chromatograpy to give the title compound (0.44 g,64%) as an oil and3-(1-(cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazol-3-yl) propan-1-ol(0.21 g, 31%) as a minor product. ¹H NMR (300 MHz, CDCl₃) δ 7.24-7.33(m, 4H), 6.66 (dt, J=1.2 and 16.0 Hz, 1H), 6.32-6.42 (m, 1H), 6.32 (s,1H), 4.31 (dd, J=1.3 and 5.7 Hz, 2H), 3.88 (d, J=7.4 Hz, 2H), 2.53 (s,3H), 1.75-1.93 (m, 1H), 1.40-1.84 (m, 5H), 0.98-1.28 (m, 3H), 0.64-0.83(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 149.1, 144.8, 139.5, 130.2, 129.5,127.5, 126.3, 123.4, 103.0, 63.5, 55.6, 38.9, 30.6, 26.3, 25.7, 15.5;mass spectrum (API-TIS) m/z 343 (MH⁺); Anal. Calcd for C₂₀H₂₆N₂OS: C,70.14; H, 7.65; N, 8.18. Found: C, 70.13; H, 7.72; N, 8.18.

[1218] 4d.1-(3-((1E)-3-Hydroxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1219] The product of Example 4c (0.44 g, 1.29 mmol) was dissolved inMeOH (16 mL). OXONE® (1.58 g, 2.57 mmol) in water (3 mL) was added atroom temperature. The reaction mixture was stirred for 1 hour and thenfiltered to remove the solid. CH₂Cl₂ was added to the filtrate which waswashed with saturated NaHCO₃, water, dried over Na₂SO₄ and filtered. Thesolvent was evaporated to give the product (0.23 g, 48%) as a whitefoam; mp 49-52° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.1 Hz, 2H),7.59 (d, J=8.2 Hz, 2H), 6.66 (d, J=16.1 Hz, 1H), 6.41 (s, 1H), 6.32-6.47(m, 1H), 4.32 (bd, J=5.2 Hz, 2H), 3.91 (d, J=7.3 Hz, 2H), 3.12 (s, 3H),1.78-1.97 (m, 1H), 1.41-1.69 (m, 5H), 0.98-1.30 (m, 3H), 0.65-0.83 (m,2H); ¹³C NMR (75 MHz, CDCl₃) 8149.5, 143.3, 140.5, 136.6, 130.7, 130.0,127.9, 123.1, 104.0, 63.5, 56.0, 44.6, 39.0, 30.6, 26.3, 25.7; massspectrum (API-TIS) m/z 375 (MH⁺); Anal. calcd for C₂₀H₂₆N₂O₃S: C, 64.14;H, 7.00; N, 7.48. Found: C, 64.11; H, 6.91; N, 7.40.

[1220] 4e.1-(3-((1E)-3-Nitrooxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1221] Fuming HNO₃ (0.34 mL, 0.50 g, 8.0 mmol) was added dropwise to asolution of the product from Example 4d (0.1 g, 0.27 mmol) in CHCl₃ (4mL) at −10° C. and then stirred at −10° C. for 1 hour. The solution wasdiluted with CH₂Cl₂ and washed with ice cold saturated NaHCO₃, water,dried over Na₂SO₄, and filtered. The residue after evaporation of thesolvent purified by chromatography over silica gel eluting with 1:2EtOAc:Hexane to give the product as a white foam (0.70 mg, 62%); mp44-47° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d, J=8.4 Hz, 2H), 7.59 (d,J=8.4 Hz, 2H), 6.82 (d, J=16.0 Hz, 1H), 6.44 (s, 1H), 6.24-6.32 (m, 1H),5.08 (d, J=6.1 Hz, 2H), 3.92 (d, J=7.3 Hz, 2H), 3.13 (s, 3H), 1.80-1.95(m, 1H), 1.35-1.95 (m, 5H), 0.95-1.25 (m, 3H), 0.60-0.82 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 148.2, 143.6, 140.8, 136.4, 130.14, 130.07, 128.1,120.6, 104.7, 73.6, 58.5, 44.6, 33.5, 27.3, 25.7, 25.2; mass spectrum(API-TIS) m/z 420 (MH⁺). Anal. calcd for C₂₀H₂₅N₃O₅S.¼ mol H₂O: C,56.66; H, 6.06; N, 9.91. Found: C, 56.80; H, 5.99; N, 9.85.

Example 53-(1-(Cyclohexylmethyl)-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1222] 5a.3-(1-(Cyclohexylmethyl)-5-(4-methylthiophenyl)pyrazol-3-yl)propan-1-ol

[1223] The title compound was prepared as a colorless oil (0.21 g, 31%)from the product of Example 4b by following the procedure for Example4c. ¹H NMR (300 MHz, CDCl₃) δ 7.207.35 (m, 4H), 6.03 (s, 1H), 3.85 (d,J=7.4 Hz, 2H), 3.74 (t, J=5.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 2.53 (s,3H), 1.94 (p, J=6.4 Hz, 2H), 1.78-1.90 (m, 1H), 1.40-1.68 (m, 5H),0.98-1.25 (m, 3H), 0.63-0.84 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 151.7,144.6, 139.2, 129.4, 127.7, 126.2, 104.8, 62.3, 55.3, 38.8, 32.1, 30.5,26.3, 25.6, 25.2, 15.4; mass spectrum (API-TIS) m/z 345 (MH⁺); Anal.calcd for C₂₀H₂₈N₂OS: C, 69.73; H, 8.19; N, 8.13. Found: C, 69.33; H,7.82; 7.74.

[1224] 5b.1-(1-(Cyclohexylmethyl)-3-(3-hydroxypropyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1225] The title compound was prepared as a white solid (0.16 g, 70%)from the product of Example 5a by following the procedure for Example4d; mp 94-95° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.3 Hz, 2H), 7.58(d, J=8.3 Hz, 2H), 6.13 (s, 1H), 3.89 (d, J=7.4 Hz, 2H), 3.74 (t, J=6.0Hz, 2H), 3.12 (s, 3H), 2.80 (t, J=7.1 Hz, 2H), 2.58 (t, J=5.7 Hz, 1H),1.95 (p, J=6.6 Hz, 2H), 1.74-1.95 (m, 1H), 1.38-1.70 (m, 5H), 0.97-1.24(m, 3H), 0.64-0.80 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 152.1, 142.9,140.2, 136.8, 129.7, 127.8, 105.8, 62.2, 55.6, 44.5, 38.9, 32.1, 30.5,26.2, 25.5, 25.0. Mass spectrum (API-TIS) m/z 377 (MH⁺). Anal. calcd forC₂₀H₂₈N₂O₃S: C, 63.80; H, 7.50; N, 7.44. Found: C, 63.75; H, 7.35; 7.29.

[1226] 5c.1-(1-(Cyclohexylmethyl)-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

[1227] The title compound was prepared as a white solid (0.1 g, 62%)from the product of Example 5b by following the procedure for Example1h; mp 76-77° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.4 Hz, 2H), 7.57(d, J=8.4 Hz, 2H), 6.13 (s, 1H), 4.54 (d, J=6.6 Hz, 2H), 3.89 (d, J=7.3Hz, 2H), 3.12 (s, 3H), 2.79 (t, J=7.3 Hz, 2H), 2.13 (p, J=6.9 Hz, 2H),1.75-1.95 (m, 1H), 1.37-1.68 (m, 5H), 0.97-1.22 (m, 3H), 0.64-0.82 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 150.6, 143.2, 140.5, 136.9, 129.9, 128.0,105.8, 72.8, 55.9, 44.7, 39.1, 30.7, 26.8, 26.3, 25.7, 24.5; massspectrum (API-TIS) m/z 422 (MH⁺); Anal. calcd for C₂₀H₂₇N₃O₅S: C, 56.99;H, 6.46; N, 9.97. Found: C, 56.83; H, 6.48; 9.79.

Example 61-(1-(Cyclohexylmethyl)-3-vinylpyrazol-5-yl)-4-(methylsulfonyl)benzene

[1228] 6a.1-(1-(Cyclohexylmethyl)-3-vinylpyrazol-5-yl)-4-methylthiobenzene

[1229] n-Butyl lithium (2.5 M solution in hexane, 0.67 mL, 0.11 g, 1.69mmol) was added dropwise to a solution of methyltriphenylphosphoniumbromide (0.51 g, 1.43 mmol) in THF (4 mL) at −78° C. The resultantsolution was stirred at −78° C. for 1 hour. To this solution the productfrom Example 4a (0.41 g, 1.3 mmol) in THF (4 mL) was added dropwise. Thereaction mixture was stirred at −78° C. for 1 hour. The reaction mixturewas gradually allowed to warm to room tmeperature and stirred for 24hours. Water was added and extracted with EtOAc, which was then washedwith water, dried over Na₂SO₄ and filtered. The residue obtained afterevaporation of the solvent was purified by chromatography over silicagel eluting with 0.5:10 EtOAc:Hexane to give the title compound (0.1 g,25%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.35 (m, 4H),6.70-6.84 (m, 1H), 6.38 (s, 1H), 5.73 (dd, J=1.3, 18.0 Hz, 1H), 5.30(dd, J=0.8, 10.8 Hz, 1H), 3.91 (d, J=7.3 Hz, 2H), 2.54 (s, 3H),1.78-1.97 (m, 1H), 1.38-1.64 (m, 5H), 0.92-1.25 (m, 3H), 0.63-0.84 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 150.0, 144.7, 139.4, 129.5, 127.6, 126.2,114.8, 102.5, 55.6, 38.8, 30.6, 26.3, 25.7, 15.5; mass spectrum(API-TIS) m/z 313 (MH⁺).

[1230] 6b.1-(1-(Cyclohexylmethyl)-3-vinylpyrazol-5-yl)-4-(methylsulfonyl)benzene

[1231] The title compound was prepared as a white solid (78 mg, 74%)from the product of Example 6a by following the procedure for Example4d; mp 136-138° C. ¹H NMR (300 MHz, CDCl₃) δ 8.03 (dd, J=1.8 and 6.8 Hz,2H), 7.59 (dd, J=1.8 and 6.8 Hz, 2H), 6.68-6.78 (m, 1H), 6.45 (s, 1H),5.74 (dd, J=1.2 and 17.8 Hz, 1H), 5.33 (dd, J=1.2 and 11.0 Hz, 1H), 3.91(d, J=7.3 Hz, 2H), 3.12 (s, 3H), 1.74-1.98 (m, 1H), 1.40-1.70 (m, 5H),1.00-1.31 (m, 3H), 0.65-0.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 150.4,143.2, 140.5, 136.6, 129.9, 129.1, 127.9, 115.4, 103.6, 55.9, 44.5,38.9, 30.5, 26.2, 25.6; mass spectrum (API-TIS) m/z 345 (MH⁺); Anal.calcd for C₁₉H₂₄N₂O₂S.¼ mol H₂O: C, 65.39; H, 7.08; N, 8.03. Found: C,65.43; H, 7.13; N, 7.95.

Example 7 Methyl(2E)-3-(1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)prop-2-enoate

[1232] 7a. Methyl(2E)-3-(1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)prop-2-enoate

[1233] The title compound was prepared as a white foam (0.24 g, 74%)from the product of Example 4b by following the procedure for Example4d; mp 48-50° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J=8.3 Hz, 2H), 7.70(d, J=16.0 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 6.54 (s, 1H), 6.44 (d,J=16.0 Hz, 1H), 3.95 (d, J=7.3 Hz, 2H), 3.81 (s, 3H), 3.13 (s, 3H),1.80-1.95 (m, 1H), 1.38-1.70 (m, 5H), 0.98-1.27 (m, 3H), 0.62-0.87 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 167.4, 147.5, 143.7, 140.9, 136.7, 136.1,130.1, 128.1, 119.1, 106.0, 56.3, 51.8, 44.6, 39.0, 30.6, 26.2, 25.7;mass spectrum (API-TIS) m/z 403 (MH⁺); Anal. calcd for C₂₁H₂₆N₂O₄S: C,62.66; H, 6.51; N, 6.96. Found: C, 62.40; H, 6.49; N, 6.84.

Example 8 Methyl5-(4-(methylsulfonyl)phenyl)-1-benzylpyrazole-3-carboxylate

[1234] 8a. Methyl5-(4-(methylsulfonyl)phenyl)-1-benzylpyrazole-3-carboxylate

[1235] The title compound was prepared from the product of Example 3a byfollowing the procedure for Example 4d to give a white solid (0.23 g,63% yield); mp 142-143° C. ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.1 Hz,2H), 7.48 (d, J=8.1 Hz, 2H), 7.27-7.28 (m, 3H), 6.98-7.02 (m, 2H), 6.98(s, 1H), 5.45 (s, 2H), 3.98 (s, 3H), 3.08 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 162.6, 143.5, 143.4, 141.3, 136.1, 135.0, 129.9, 129.0, 128.2,128.0, 126.8, 110.4, 54.7, 52.4, 44.6; mass spectrum (API-TIS) m/z 371(MH⁺), 387 (MNH₄ ⁺); Anal. Calcd for Cl₉H₁₈N₂O₄S: C, 61.61; H, 4.90; N,7.56, S, 8.65. Found: C, 61.36; H, 4.85; N, 7.46; S, 8.95.

Example 9 3-(4-(Methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl)Phenyl Ketone and2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrile

[1236] 9a. 3-(4-(Methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl)Phenyl Ketone

[1237] To2-(3-Chloro-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrile (RyanScientific Inc., South Carolina, U.S., 4.8 g, 16.17 mmol) and4-(methylthio)benzeneboronic acid (4.15 g, 25 mmol) dissolved inanhydrous dioxane (80 mL) were added successively,tris(dibenzylideneacetone)dipalladium (0.58 g, 0.633 mmol),tri-tert-butylphosphine (150 mg, 0.724 mmol) followed by cesiumcarbonate (6.5 g, 20 mmol). The resulting mixture was heated at refluxovernight under a nitrogen atmosphere. Additional4-(methylthio)benzeneboronic acid (4.15 g, 25 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.58 g, 0.633 mmol),tri-tert-butylphosphine (150 mg, 0.724 mmol) and cesium carbonate (6.5g, 20 mmol) were added and the reaction mixture was heated at reflux foranother 24 hours, then cooled to room temperature and solvent wasevaporated. The residue was treated with water and then extracted withethyl acetate (1×250 mL). The combined organic extracts were washed withwater (4×250 mL), brine (1×250 mL), dried over sodium sulfate, treatedwith charcoal, filtered and concentrated to give the crude product.Purification by column chromatography over silica gel using 5% ethylacetate in hexane gave a thick oil (1.3 g) that was a mixture (85:15) of2-(3-(4-methylthiophenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrileand 3-(4-methylthiophenyl)-5-(trifluoromethyl)(2-pyridyl) phenyl ketone.This mixture was dissolved in methanol (60 mL) and OXONE® (4.35 g, 7.1mmol) in water (15 mL) was added, and then stirred at room temperaturefor 1.5 hours. The resulting mixture was neutralized with ammoniumhydroxide, the solvent was evaporated and the residue extracted withethyl acetate (2×50 mL). The combined organic extracts were washed withwater (2×50 mL), brine (1×25 mL), dried over sodium sulfate, filteredand solvent was evaporated to give the crude product. Purification bycolumn chromatography over silica gel using a gradient of 20 to 40%ethyl acetate in hexane gave the less polar compound,3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl) phenylketone, as a white crystalline product (85 mg), mp 141-142° C. ¹H NMR(CDCl₃) δ 9.03 (s, 1H), 8.14 (d, J=1.3 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H),7.85 (dd, J=7.2 and 1.0 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.58 (d, J=8.3Hz, 2H), 7.51 (t, J=7.5 Hz, 2H), 3.03 (s, 3H); ¹³C NMR (CDCl₃) δ 193.1,158.2, 145.05, 141.5, 140.7, 135.3, 134.3, 130.3 (2C), 129.7 (2C), 128.2(2C), 127.8, (2C), 127.0 (q, J=33 Hz, CF₃), 124.6, 121.0, 44.3; LRMS(APIMS) m/z 406 (M+H)⁺.

[1238] 9b.2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrile

[1239] Purification of the more polar fractions of the product ofExample 9a by column chromatography over silica gel using a gradient of20 to 40% ethyl acetate in hexane gave the title compound,2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2phenylethanenitrile,490 mg, as a light yellow solid; mp 78° C.; ¹H NMR (CDCl₃) δ 9.05 (s,1H), 8.10 (d, J=1.6 Hz, 2H), 7.80 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.33(m, 3H), 7.16 (m, 2H), 5.42 (s, 1H), 3.18 (s, 3H); ¹³C NMR (CDCl₃) δ155.0, 146.6, 141.6, 141.4, 135.5, 135.1, 133.6, 130.1 (2C), 129.2 (2C),128.1, 127.8, (2C), 127.0 (2×C), 126.3 (q, J=33 Hz, CF₃), 124.6, 121.0,118.1, 44.4, 42.3; LRMS (APIMS) m/z 417 (M+H)⁺.

Example 10 3-Fluorophenyl 2-(4-(methylsulfonyl)phenyl)(3-pyridyl) ketone

[1240] 10a. 2-Chloro(3-pyridyl) 3-fluorophenyl Ketone

[1241] The Grignard reagent was prepared by refluxing1-bromo-3-fluorobenzene (1.75 g, 10 mmol) and magnesium metal (267 mg,11 mmol) and a few crystals of iodine in anhydrous THF (40 mL) undernitrogen atmosphere until most of the magnesium metal was consumed. Thereagent was cooled to room temperature and 2-chloro-3-nicotinoylchloride (1.76 g, 10 mmol) in anhydrous THF (20 mL) was added and theresulting mixture was stirred at room temperature for 15 minutes andthen quenched with saturated aqueous ammonium chloride solution. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and the filtrate concentrated to givethe crude product. Purification by flash column chromatography using 20%ethyl acetate in hexane gave the title compound (2.35 g) in nearlyquantitative yield, as a colorless thick oil. ¹H NMR (CDCl₃) δ 8.54 (dd,J=5.0, 3.0 Hz, 1H), 7.73 (dd, J=7.5, 1.9 Hz, 1H), 7.5-7.2 (m, 5H); ¹³CNMR (CDCl₃) δ 192.0, 164.4, 161.1, 151.1, 147.6, 139.9, 134.3, 130.4,(d, J_(C-F)=7.5 Hz), 125.8, 122.3, 121.2 (d, J_(C-F)=22 Hz), 116.2 (d,J_(C-F)=22 Hz); LRMS (APIMS) m/z 236 (M+H)⁺.

[1242] 10b. 3-Fluorophenyl 2-(4-methylthiophenyl)(3-pyridyl) Ketone

[1243] The product of Example 10a (1.41 g, 6 mmol) and4-(methylthio)benzeneboronic acid (1.66 g, 10 mmol) were dissolved intoluene (125 mL) and 2 M Na₂CO₃ (6 mL, 12 mmol) was added. To thismixture was added ethanol (10 mL) followed by tetrakis(triphenylphosphine) palladium (450 mg, 0.4 mmol) and the mixture wasrefluxed overnight under nitrogen atmosphere. The mixture was thencooled to room temperature and diluted with water (25 mL), stirred, andthe aqueous layer was separated and extracted with ethyl acetate (1×75mL). The combined organic layers were washed with water (4×50 mL), brine(1×50 mL), dried over sodium sulfate, filtered and concentrated atreduced pressure to give the crude product. Purification by columnchromatography over silica gel using 20% ethyl acetate in hexane gavethe title compound (900 mg, 46% yield) as a white solid; mp 91-92° C.;¹H NMR (CDCl₃) δ 8.88 (dd, J=4.8, 1.7 Hz, 1H), 7.88 (dd, J=7.6, 1.6 Hz,1H), 7.5-7.35 (m, 5H), 7.3-7.25 (m, 1H), 7.2-7.15 (m, 3H), 2.51 (s, 3H);LRMS (APIMS) m/z 324 (M+H)⁺.

[1244] 10c. 3-Fluorophenyl 2-(4-methylsulfonylphenyl)(3-pyridyl) ketone

[1245] The product of Example 10b (650 mg, 1.857 mmol) was dissolved inMeOH (40 mL). To this solution, OXONE® (2.848 g, 4.64 mmol) dissolved inH₂O (10 mL) was added. The mixture was stirred at room temperature for1.5 hours, then diluted with water, and ammonium hydroxide added untilthe solution became basic. The solvent was evaporated and the productwas extracted with ethyl acetate (2×75 mL), washed with brine (1×50 mL),dried over anhydrous sodium sulfate, filtered and solvent evaporated atreduced pressure to give an oil which upon trituration with hexane/ethylacetate gave the title compound (650 mg, 99% yield); mp 157-159° C.; ¹HNMR (CDCl₃) δ 8.92 (d, J=4.7 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.88 (d,J=7.6 Hz, 2H), 7.74 (d, J=7.8 Hz, 2H), 7.53 (dd, J=7.7, 4.8 Hz, 1H),7.47-7.3 (m, 3H), 7.2 (m, 1H), 3.18 (s, 3H); ¹³C NMR (CDCl₃) δ 195.1,164.1, 160.8, 155.4, 151.3, 144.3, 140.5, 138.3, (d, J=6.4 Hz), 137.1,134.1, 130.1 (2C), 128.1 (2C), 125.7, (d, J=3 Hz), 122.5, 120.8 (d,J=21.5 Hz), 116.2 (d, J=22 Hz), 44.4; LRMS (APIMS) m/z 356 (M+H)⁺.

Example 11 2-(4-(Methylsulfonyl)phenyl)(3-pyridyl) 2-pyridyl Ketone

[1246] 11a. 2-(4-Methylthiophenyl)(3-pyridyl) 2-pyridyl Ketone

[1247] 2-Chloro(3-pyridyl) 2-pyridyl ketone (Ryan Scientific Inc., SouthCarolina, U.S.) (810 mg, 3.7 mmol) and 4-(methylthio)benzeneboronic acid(830 mg, 5 mmol) were dissolved in toluene (50 mL) and ethanol (5 mL).To this solution was added 2 M Na₂CO₃ (6 mL, 12 mmol) followed bytetrakis (triphenylphosphine)palladium (250 mg, 0.2 mmol) and theresulting mixture was refluxed overnight under nitrogen atmosphere. Themixture was then cooled to room temperature and diluted with water (25mL), stirred and the aqueous layer was separated and extracted withethyl acetate (1×75 mL). The combined organic layers were washed withwater (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filteredand concentrated at reduced pressure to give the crude product.Purification by column chromatography over silica gel using 40% ethylacetate in hexane gave the title compound (770 mg, 68% yield) as a whitesolid; mp 122-123° C.; ¹H NMR (CDCl₃) δ 8.87 (dd, J=4.8 and 1.7 Hz, 1H),8.45 (d, J=4.7 Hz, 1H), 8.0 (dd, J=7.7 and 1.4 Hz, 2H), 7.75 (m, 1H),7.45-7.3 (m, 4H), 7.12 (d, J=8.4 Hz, 2H), 2.44 (s, 3H); ¹³C NMR (CDCl₃)δ 196.0, 157.6, 153.5, 150.7, 148.8, 139.3, 137.4, 136.6, 136.5, 133.6,129.4 (2C), 126.5, 125.7 (2C), 123.5, 121.1, 15.3; LRMS (APIMS) m/z 307(M+H)⁺.

[1248] 11b. 2-(4-(Methylsulfonyl)phenyl)(3-pyridyl) 2-pyridyl Ketone

[1249] The product of Example 11a (670 mg, 2.2 mmol) was dissolved inMeOH (50 mL). To this solution, OXONE® (3.07 g, 5 mmol) dissolved in H₂O(20 mL) was added. The reaction mixture was stirred at room temperatureovernight, it was then diluted with water, ammonium hydroxide addeduntil the solution became basic and the solvent was evaporated. Theproduct was extracted with ethyl acetate (2×75 mL), washed with brine(1×50 mL), dried over anhydrous sodium sulfate, filtered and solventevaporated at reduced pressure to give an oil which upon triturationwith hexane:ethyl acetate (80:20) gave the title compound (670 mg, 99%)as a white solid; mp 143-147° C.; ¹H NMR (CDCl₃) δ 8.90 (dd, J=4.8 and1.6 Hz, 1H), 8.43 (d, J=4.3 Hz, 1H), 8.06 (d, J=7.7, 2H), 7.80 (m, 3H),7.71 (d, J=8.4 Hz, 2H), 7.52 (dd, J=7.7 and 4.8 Hz, 1H), 7.3 (m, 1H),3.0 (s, 3H); ¹³C NMR (CDCl₃) δ 196.2, 156.4, 153.1, 150.9, 148.9, 145.5,140.1, 137.7, 136.9, 134.3, 130.1 (2C), 127.1 (2C), 127.0, 123.7, 122.4,44.4; LRMS (APIMS) m/z 339 (M+H)⁺.

Example 12 Ethyl3-((2-(4-(methylsulfonyl)phenyl)-3-pyridyl)carbonyl)benzoate

[1250] 12a. Ethyl 3-((2-(4-methylthiophenyl)-3-pyridyl)carbonyl)benzoate

[1251] To ethyl 3-((2-chloro-3-pyridyl)carbonyl)benzoate (RyanScientific Inc., South Carolina, U.S., 950 mg, 3.3 mmol) in ethanol (5mL) was added 2 M Na₂CO₃ (3.3 mL, 6.6 mmol) followed by tetrakis(triphenylphosphine)palladium (250 mg, 0.2 mmol) and the resultingmixture was refluxed overnight under nitrogen atmosphere. The mixturewas then cooled to room temperature and diluted with water (25 mL),stirred and the aqueous layer was separated and extracted with ethylacetate (1×75 mL). The combined organic layers were washed with water(2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered andevaporated to give the crude product. Purification by columnchromatography over silica gel using 10% ethyl acetate in hexane gavethe title compound (1.24 g) as a thick oil in nearly quantitative yield.¹H NMR (CDCl₃) δ 8.9 (dd, J=7.8, 1.8 Hz, 1H), 8.31 (s, 1H), 8.16 (dt,J=7.9, 1.4 Hz, 1H), 7.91 (dd, J=7.7, 1.8 Hz, 1H), 7.88 (dt, J=7.9 and1.4 Hz, 1H), 7.5-7.4 (m, 4H), 7.15 (d, J=7.7 Hz, 2H), 4.40 (q, J=7.1 Hz,2H), 2.43 (s, 3H), 1.42 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 196.4,165.4, 156.9, 151.1, 140.1, 137.2, 136.7, 135.7, 134.0, 133.6, 130.8,129.5 (2×C), 128.6, 125.9, (2C), 121.5, 61.3, 15.3 14.2; LRMS (APIMS)m/z 378 (M+H)⁺.

[1252] 12b. Ethyl3-((2-(4-(methylsulfonyl)phenyl)-3-pyridyl)carbonyl)benzoate

[1253] To the product of Example 12a (1.3 g, 3.44 mmol) in MeOH (180 mL)was added OXONE® (6.14 g, 10 mmol) dissolved in H₂O (50 mL). Theresulting mixture was stirred at room temperature for 1 hour, thendiluted with water, and ammonium hydroxide was added until the solutionbecame basic and the solvent was evaporated. The product was extractedwith ethyl acetate (2×75 mL), washed with brine (1×50 mL), dried overanhydrous sodium sulfate, filtered and solvent evaporated to give an oilwhich upon trituration with hexane:ethyl acetate (90:10) gave the titlecompound (1.34 g, 95% yield) as a white solid; mp 125-132° C.; ¹H NMR(CDCl₃) δ 8.92 (dd, J=4.5, 1.1 Hz, 1H), 8.30 (s, 1H), 8.16 (d, J=7.7 Hz,1H), 7.96 (dd, J=7.7, 1.41 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.84 (d,J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.54 (dd, J=7.7, 4.9 Hz, 1H),7.46 (t, J=7.2 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.97 (s, 3H), 1.41 (t,J=7.2 Hz, 3H); ¹³C NMR (CDCl₃) δ 195.5, 165.1, 155.5, 151.3, 144.4,140.4, 137.3, 136.4, 134.3, 134.1, 133.5, 131.0, 130.9, 130.1 (2C),128.9, 127.3 (2C), 122.7, 61.4, 44.3, 14.2; LRMS (APIMS) m/z 410 (M+H)⁺.

Example 13 Assay for Human COX-1 and COX-2 Enzyme Activity in HumanWhole Blood

[1254] The assay for COX-1 and COX-2 enzyme activity, in the human wholeblood was performed as described in Brideau et al., Inflamm Res., 45:68-74 (1996)). Human blood (≈50 mL) from male or female donors who hadnot received any aspirin or NSAIDs for 14 days was collected at twolocal area blood donor centers and placed in polypropylene syringescontaining sodium heparin (20 units per mL blood, final concentration).The blood was transported to the laboratory on ice packs and used within1.5 hours of collection. Upon receipt in the laboratory, the blood wasallowed to come to room temperature for 15 minutes prior to distributionin 1 mL aliquots per well of 24 well tissue culture plates. The plateswere then placed on a gently rotating platform shaker in a 5% CO₂incubator at 37° C. for 15 minutes. Test compounds were dissolved inDMSO, at 1000 fold the final desired concentration, and further diluted,as indicated, in DMSO. One μL of each dilution of the test compound wasadded per well, in duplicate wells; wells not receiving test compound(e.g., basal, background or control wells) received 1 μL DMSO.

[1255] To induce COX-2, lipopolysaccharide (LPS) from E. coli (LPS,serotype 026:B6 or serotype 0127:B8, Sigma Chemical Co., St. Louis, Mo.,Catalogue No. L3755 or L3129, respectively) was added at 10 μg/mL (2 μLof 5 mg/mL LPS in DMSO) to appropriate wells 15 minutes after theaddition of the test compound. (Basal or background wells not incubatedwith LPS received 2 μL of DMSO.) For the stimulation of COX-1, thecalcium ionophore, A23187 (free acid from Sigma Chemical Co., St. Louis,Mo., Catalogue No. C7522) was added at 25 μM (1 μL of 25 mM stock inDMSO) to separate wells 4.5 hours after the addition of the testcompound. (Again, basal, background or control wells not stimulated withA23187 received 1 μL of DMSO.) At 5 hours after the addition of the testcompound, all incubations were terminated by placement on ice and theaddition of 2 mM EGTA (100 μL of 20 mM EGTA, tetrasodium, in PBS(phosphate buffered saline) without Ca⁺⁺ and Mg⁺⁺, pH 7.2)). Theresulting solutions, were transferred by polyethylene transfer pipettesto 15 mL polypropylene centrifuge tubes and centrifuged at 1200 g for 10minutes at 4° C. One hundred μL of plasma was removed from each bloodsample and added to 1 mL of methanol in new 15 mL polypropylenecentrifuge tubes, vortexed, and stored overnight at −20° C. The nextday, the samples were centrifuged at 2000 g for 10 minutes at 4° C. andthe supernatants transferred to glass tubes and evaporated to dryness.The samples were assayed for thromboxane B₂ using EIA kits supplied byCayman Chemical Co. (Ann Arbor, Mich., Catalogue No. 519031) induplicate wells after reconstitution with EIA Buffer and appropriatedilution (2000 fold for COX-1 and 500 fold for Cox-2 samples).

[1256] The % inhibition for COX-1 and COX-2 enzyme activity in humanwhole blood by the test compounds, at the indicated concentrations, aregiven in Table 1. TABLE 1 % INHIBITION OF COX-1 AND COX-2 ENZYMEACTIVITY IN HUMAN WHOLE BLOOD Test COX-1 Inhibition COX-2 InhibitionCOX-2 Inhibition Compound (% at 100 μM) (% at 10 μM) (% at 1 μM) Example1g 65 45 0 Example 1h 25 65 10 Example 2e 65 65 25 Example 2f 70 75 20Example 3c 25 15 10 Example 3d 55 40 20 Example 4d 50 45 25 Example 4e40 75 35 Example 5b 90 90 45 Example 5c 90 100 75 Example 6b 30 100 70Example 7 5 30 15 Example 8 55 25 15 Example 9a 90 90 60 Example 9b −1055 35 Example 10c 5 50 55 Example 11b 0 15 0 Example 12b 25 20 10

[1257] The results show that the compounds in Table 1 have COX-2selectivity.

Example 10 Rat Carrageenan Air-Pouch

[1258] The carrageenan air pouch model was performed as described bySedgwick, A. D., et al., Agents Actions 18, 429-438, (1986) andMasferrer et al., Proc. Natl. Acad. Sci. 91, 3228-3232 (1994). Airpouches were produced by subcutaneous injection of 20 ml of sterile airon day (−6) into the intrascapular area of the back of the anesthesiarat (male CD, Charles River, 175-200 g). An additional 10 mL of sterileair was injected into the pouch 3 days later to keep the space open andto assist in the development of the interior membrane. Six days afterthe initial air injection, 1 mL of a 1% solution of carrageenan (Sigma,lambda fraction) dissolved in pyrogen-free saline was injected directlyinto the pouch to produce an inflammatory response. The test compound invehicle (3 mL/rat, 0.5% Methocel) was administered by oral intubation 1hour prior to carrageenan injection into the inflammatory pouch. After 4hours the exudate was removed by pipette into a calibrated centrifugetube and the volume measured. The number of leukocytes in the exudatewas determined by cell counting with a Beckman Coulter Particle Counterwith the lower threshold set to exclude red blood cells. The exudatesamples were assayed without further processing for PGE₂ (prostaglandinE₂) using PGE₂ EIA kit-Monoclonal, friom Cayman Chemical Co. (Ann Arbor,Mich., Catalogue No. 514010).

[1259] The % inhibition for the cell infiltration and the % inhibitionfor PGE₂ by the test compounds, at the indicated concentrations, aregiven in Table 2. TABLE 2 Test Cell Infiltration (% PGE-2 Compoundinhibition @ 45 μmol/kg) (% Inhibition at @ 45 μmol/kg) Example 2f 42 85

[1260] The compound in Table 2 inhibited cell infiltration with anaccompanying decrease in PGE₂ levels.

[1261] The disclosure of each patent, patent application and publicationcited or described in the present specification is hereby incorporatedby reference herein in its entirety.

[1262] Although the invention has been set forth in detail, one skilledin the art will appreciate that numerous changes and modifications canbe made to the invention, and that such changes and modifications can bemade without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII), or a pharmaceutically acceptable saltthereof; wherein the compound of Formula (I) is:

wherein: when side b is a double bond, and sides a and c are singlebonds, —X¹-Y¹-Z¹- is: (a) —CR⁴(R⁵)—CR⁵(R⁵′)—CR⁴(R⁵)—; (b)—C(O)—CR⁴(R⁴′)—CR⁵(R⁵′)—; (c) —CR⁴(R⁴′)—CR⁵(R⁵′)—C(O)—; (d)—(CR⁵(R⁵′))_(k)—O—C(O)—; (e) —C(O)—O—(CR⁵(R⁵′))_(k)—; (f)—CR⁴(R⁴′)—NR³—CR⁵(R⁵′)—; (g) —CR⁵(R⁵′)—NR³—C(O)—; (h) —CR⁴═CR⁴′—S—; (i)—s—CR⁴═CR⁴′—; (j) —S—N═CR⁴—; (k) —CR⁴═N—S—; (l) —N═CR⁴—O—; (m)—O—CR⁴═N—; (n) —NR³—CR⁴═N—; (o) —N═CR⁴—S—; (p) —S—CR⁴═N—; (q)—C(O)—NR³—CR⁵′(R^(5′))—; (r) —R³N—CR⁵═CR⁵′—; (s) —CR⁴═CR⁵—NR³—; (t)—O—N═CR⁴—; (u) —CR⁴═N—O—; (v) —N═N—S—; (w) —S—N═N—; (x) —N═CR⁴—NR³—; (y)—R³N—N═N—; (z) —N═N—NR³—; (aa) —CR⁴(R^(4′))—O—CR⁵(R⁵′)—; (bb)—CR⁴(R^(4′))—S—CR⁵(R⁵′)—; (cc) —CR⁴(R^(4′))—C(O)—CR⁵(R⁵′)—; (dd)—CR⁴(R^(4′))—CR⁵(R⁵′)—C(S)—; (ee) —(CR⁵(R⁵′))_(k)—O—C(S)—; (ff)—C(S)—O—(CR⁵(R⁵′))_(k)—; (gg) —(CR⁵(R⁵′))_(k)—NR³—C(S)—; (hh)—C(S)—NR³—(CR⁵(R⁵′))_(k)—; (ii) —(CR⁵(R⁵′))_(k)—S—C(O)—; (jj)—C(O)—S—(CR⁵(R⁵′))_(k)—; (kk) —O—CR⁴═CR⁵; (ll) —CR⁴═CR⁵—O—; (mm)—C(O)—NR³—S—; (nn) —S—NR³OC(O)—; (oo) —C(O)—NR³—O—; (pp) —O—NR³—C(O)—;(qq) —NR³—CR⁴═CR⁵—; (rr) —CR⁴═N—NR³—; (ss) —NR³—N═CR⁴—; (tt)—C(O)—NR³—NR³—; (uu) —NR³—NR³—C(O)—; (vv) —C(O)—O—NR³—; (ww) —NR³—C(O)—;(xx) —O—CR⁴R^(4′)—C(S)—; (zz) —O—CR⁴R^(4′)—C(O)—; (aaa)—C(S)—CR⁴R^(4′)—O—; or (yy) —C(O)—CR⁴R^(4′)—O—; when sides a and c aredouble bonds and side b is a single bond, —X¹-Y¹-Z¹- is: (a)═CR⁴—O—CR⁵═; (b) ═CR⁴—NR³—CR⁵═; (c) ═N—S—CR⁴═; (d) ═CR⁴—S—N═; (e)═N—O—CR⁴═; (f) ═CR⁴—O—N═; (g) ═N—S—N═; (h) ═N—O—N═; (i) ═N—NR³—CR⁴═; (j)═CR⁴—NR³—N═; (k) ═N—NR³—N═; (l) ═CR⁴—S—CR⁵═; or (m)═CR⁴—CR⁴(R^(4′))—CR⁵═; R¹ is: (a) —S(O)₂—CH₃; (b) —S(O)₂—NR⁸(D¹); (c)—S(O)₂—N(D¹)—C(O)—CF₃; (d) —S(O)—(NH)—NH(D¹); (e)—S(O)—(NH)—N(D¹)-C(O)—CF₃; (f) —P(O)(CH₃)NH(D¹); (g) —P(O)(CH₃)₂; (h)—C(S)—NH(D¹); (i) —S(O)(NH)CH₃; (j) —P(O)(CH₃)OD¹; or (k)—P(O)(CH₃)NH(D¹); R^(1′) at each occurrence is independently: (a)hydrogen; (b) halogen; (c) methyl; or (d) CH₂OH; R² is: (a) lower alkyl;(b) cycloalkyl; (c) mono-, di- or tri-substituted phenyl or naphthyl,wherein the substituents are each independently: (1) hydrogen; (2) halo;(3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl, preferably CF₃; (7)lower alkyl; (8) N₃; (9) —CO₂D¹; (10) —CO₂-lower alkyl;(11)—(C(R⁵)(R⁶))_(n)—OD¹; (12) —(C(R⁵)(R⁶))_(n)—O-lower alkyl; (13)lower alkyl-CO₂—R⁵; (14) —OD¹; (15) haloalkoxy; (16) amino; (17) nitro;(18) alkylsulfinyl; or (19) heteroaryl; (d) mono-, di- ortri-substituted heteroaryl, wherein the heteroaryl is a monocyclicaromatic ring of 5 atoms, said ring having one heteroatom which is S, O,or N, and, optionally, 1, 2, or 3 additional N atoms; or the heteroarylis a monocyclic ring of 6 atoms, said ring having one heteroatom whichis N, and, optionally, 1, 2, 3, or 4 additional N atoms; wherein thesubstituents are each independently: (1) hydrogen; (2) halo; (3) loweralkyl; (4) alkoxy; (5) alkylthio; (6) CN; (7) haloalkyl, preferably CF₃;(8) N₃; (9) —C(R⁵)(R⁶)—OD¹; (10) —C(R⁵)(R⁶)—O-lower alkyl; or (11)alkylsulfinyl; (e) benzoheteroaryl which includes the benzo fusedanalogs of (d); (f) —NR¹⁰R¹¹; (g) —SR¹¹; (h) —OR¹¹; (i) —R¹¹; (j)alkenyl; (k) alkynyl; (l) unsubstituted, mono-, di-, tri- ortetra-substituted cycloalkenyl, wherein the substituents are eachindependently: (1) halo; (2) alkoxy; (3) alkylthio; (4) CN; (5)haloalkyl, preferably CF₃; (6) lower alkyl; (7) N₃; (8) —CO₂D¹; (9)—CO₂-lower alkyl; (10) —C(R¹²)(R¹³)—OD; (11) —C(R¹²)(R¹³)—O-lower alkyl;(12) lower alkyl-CO₂—R¹²; (13) benzyloxy; (14) —O-(lower alkyl)-CO₂R¹²;(15) —O-(lower alkyl)-NR¹² R³; or (16) alkylsulfinyl; (m) mono-, di-,tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members,or a benzoheterocycle, wherein said heterocycloalkyl or benzoheterocyclecontains 1 or 2 heteroatoms selected from O, S, or N and, optionally,contains a carbonyl group or a sulfonyl group, and wherein saidsubstituents are each independently: (1) halo; (2) lower alkyl; (3)alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl, preferably CF₃; (7) N₃;(8) —C(R¹²)(R¹³)—OD¹; (9) —C(R¹²)(R¹³)—O-lower alkyl; or (10)alkylsulfinyl; (n) styryl, mono or di-substituted styryl, wherein thesubstituent are each independently: (1) halo; (2) alkoxy; (3) alkylthio;(4) CN; (5) haloalkyl, preferably CF₃; (6) lower alkyl; (7) N₃; (8)—CO₂D¹; (9) —CO₂-lower alkyl; (10) —C(R¹²)(R³)—OD¹; (11) —C(R2)(R¹³)—O-lower alkyl; (12) lower alkyl-CO₂—R¹²; (13) benzyloxy; (14)—O-(lower alkyl)-CO₂R¹²; or (15) —O-(lower alkyl)-NR²R¹³; (o)phenylacetylene, mono- or di-substituted phenylacetylene, wherein thesubstituents are each independently: (1) halo; (2) alkoxy; (3)alkylthio; (4) CN; (5) haloalkyl, preferably CF₃; (6) lower alkyl; (7)N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl; (10) —C(R¹²)(R³)—OD¹; (11)—C(R¹²)(R¹³)—O-lower alkyl; (12) lower alkyl-CO₂—R¹²; (13) benzyloxy;(14) —O-(lower alkyl)-CO₂R¹²; or (15) —O-(lower alkyl)-NR¹²R¹³; (p)fluoroalkenyl; (q) mono- or di-substituted bicyclic heteroaryl of 8, 9or 10 members, containing 2, 3, 4 or 5 heteroatoms, wherein at least oneheteroatom resides on each ring of said bicyclic heteroaryl, saidheteroatoms are each independently O, S and N and said substituents areeach independently: (1) hydrogen; (2) halo; (3) lower alkyl; (4) alkoxy;(5) alkylthio; (6) CN; (7) haloalkyl, preferably CF₃; (8) N₃; (9)—C(R⁵)(R⁶)—OD¹; or (10) —C(R⁵)(R⁶)—O-lower alkyl; (r) K; (s) aryl; (t)arylalkyl; (u) cycloalkylalkyl; (v) —C(O)R¹; (u) hydrogen; (v)arylalkenyl; (w) arylalkoxy; (x) alkoxy; (y) aryloxy; (z) cycloalkoxy;(aa) arylthio; (bb) alkylthio; (cc) arylalkylthio; or (dd)cycloalkylthio; R³ is: (a) hydrogen; (b) haloalkyl, preferably CF₃; (c)CN; (d) lower alkyl; (e) —(C(R_(e))(R_(f)))_(p)—U-V; (f) K; (g)unsubstituted or substituted: (1) lower alkyl-Q; (2) lower alkyl-O-loweralkyl-Q; (3) lower alkyl-S-lower alkyl-Q; (4) lower alkyl-O-Q; (5) loweralkyl-S-Q; (6) lower alkyl-O-V; (7) lower alkyl-S-V; (8) loweralkyl-O-K; or (9) lower alkyl-S-K; wherein the substituent(s) reside onthe lower alkyl group; (h) Q; (i) alkylcarbonyl; (j) arylcarbonyl; (k)alkylarylcarbonyl; (l) arylalkylcarbonyl; (m) carboxylic ester; (n)carboxamido; (o) cycloalkyl; (p) mono-, di- or tri-substituted phenyl ornaphthyl, wherein the substituents are each independently: (1) hydrogen;(2) halo; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl, preferablyCF₃; (7) lower alkyl; (8) N₃; (9) —CO₂D¹; (10) —CO₂-lower alkyl; (11)—(C(R⁵)(R⁶))_(z)—OD¹; (12) —(C(R⁵)(R⁶))_(n)—O-lower alkyl; (13) loweralkyl-CO₂—R⁵; (14) —OD¹; (15) haloalkoxy; (16) amino; (17) nitro; or(18) alkylsulfinyl; (q) alkenyl; (r) alkynyl; (s) arylalkyl; (t) loweralkyl-OD¹; (u) alkoxyalkyl; (v) aminoalkyl; (w) lower alkyl-CO₂R¹⁰; (x)lower alkyl-C(O)NR¹⁰(R¹⁰); (y) heterocyclicalkyl; or (z) heterocyclicring-C(O)—; R⁴, R⁴′, R⁵ and R⁵′ are each independently: (a) hydrogen;(b) amino; (c) CN; (d) lower alkyl; (e) haloalkyl; (f) alkoxy; (g)alkylthio; (h) Q; (i) —O-Q; (j) —S-Q; (k) K; (l) cycloalkoxy; (m)cycloalkylthio; (n) unsubstituted, mono-, or di-substituted phenyl orunsubstituted, mono-, or disubstituted benzyl, wherein the substituentsare each independently: (1) halo; (2) lower alkyl; (3) alkoxy; (4)alkylthio; (5) CN; (6) haloalkyl, preferably CF₃; (7) N₃; (8) Q; (9)nitro; or (10) amino; (o) unsubstituted, mono-, or di-substitutedheteroaryl or unsubstituted, mono-, or di-substituted heteroarylmethyl,wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, saidring having one heteroatom which is S, O, or N, and, optionally, 1, 2,or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6atoms, said ring having one heteroatom which is N, and, optionally, 1,2, 3, or 4 additional N atoms; said substituents are each independently:(1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6)haloalkyl, preferably CF₃; (7) N₃; (8) —C(R⁶)(R⁷)—OD¹; (9)—C(R⁶)(R⁷)—O-lower alkyl; or (10) alkylsulfinyl (p) —CON(R⁸)(R⁸); (q)—CH₂OR⁸; (r) —CH₂OCN; (s) unsubstituted or substituted: (1) loweralkyl-Q; (2) —O-lower alkyl-Q; (3) —S-lower alkyl-Q; (4) loweralkyl-O-lower alkyl-Q; (5) lower alkyl-S-lower alkyl-Q; (6) loweralkyl-O-Q; (7) lower alkyl-S-Q; (8) lower alkyl-O-K; (9) loweralkyl-S-K; (10) lower alkyl-O-V; or (11) lower alkyl-S-V; wherein thesubstituent(s) resides on the lower alkyl; (t) cycloalkyl; (u) aryl; (v)arylalkyl; (w) cycloalkylalkyl; (x) aryloxy; (y) arylalkoxy; (z)arylalkylthio; (aa) cycloalkylalkoxy; (bb) heterocycloalkyl; (cc)alkylsulfonyloxy; (dd) alkylsulfonyl; (ee) arylsulfonyl; (ff)arylsulfonyloxy; (gg) —C(O)R¹⁰; (hh) nitro; (ii) amino; (jj) aminoalkyl;(kk) —C(O)-alkyl-heterocyclic ring; (ll) halo; (mm) heterocyclic ring;(nn)-CO₂D¹; (oo) carboxyl; (pp) amidyl; or (qq) alkoxyalkyl;alternatively, R⁴ and R⁵ together with the carbons to which they areattached are: (a) cycloalkyl; (b) aryl; or (c) heterocyclic ring;alternatively, R⁴ and R^(4′) or R⁵ and R^(5′) taken together with thecarbon to which they are attached are: (a) cycloalkyl; or (b)heterocyclic ring; alternatively, R⁴ and R⁵, R^(4′) and R^(5′), R⁴ andR^(5′), or R^(4′) and R⁵ when substituents on adjacent carbon atomstaken together with the carbons to which they are attached are: (a)cycloalkyl; (b) heterocyclic ring; or (c) aryl; R⁶ and R⁷ are eachindependently: (a) hydrogen; (b) unsubstituted, mono- or di-substitutedphenyl; unsubstituted, mono- or disubstituted benzyl; unsubstituted,mono- or di-substituted heteroaryl; mono- or di-substitutedheteroarylmethyl, wherein said substituents are each independently: (1)halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl,preferably CF₃; (7) N₃; (8) —C(R⁴)(R¹⁵)—OD¹; or (9) —C(R¹⁴)(R¹⁵)—O-loweralkyl; (c) lower alkyl; (d) —CH₂OR⁸; (e) CN; (f) —CH₂CN; (g) haloalkyl,preferably fluoroalkyl; (h) —CON(R⁸)(R⁸); (i) halo; or (j) —OR⁸; R⁸ is:(a) hydrogen; (b) K; or (c) R⁹; alternatively, R⁵ and R⁵′, R⁶ and R⁷ orR⁷ and R⁸ together with the carbon to which they are attached form asaturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; optionallycontaining up to two heteroatoms selected from oxygen, S(O)o or NR^(i);R⁹ is: (a) lower alkyl; (b) lower alkyl-CO₂D¹; (c) lower alkyl-NHD¹; (d)phenyl or mono-, di- or tri-substituted phenyl, wherein the substituentsare each independently: (1) halo; (2) lower alkyl; (3) alkoxy; (4)alkylthio; (5) lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8)CO₂D¹; or (9) haloalkyl, preferably fluoroalkyl; (e) benzyl, mono-, di-or tri-substituted benzyl, wherein the substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8) —CO₂D¹; or (9)haloalkyl, preferably CF₃; (f) cycloalkyl; (g) K; or (h) benzoyl, mono-,di-, or trisubstituted benzoyl, wherein the substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8) —CO₂D¹; or (9)haloalkyl, preferably CF₃; R¹⁰ and R¹⁰′ are each independently: (a)hydrogen; or (b) R¹¹; R¹¹ is: (a) lower alkyl; (b) cycloalkyl; (c)unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl, whereinthe substituents are each independently: (1) halo; (2) alkoxy; (3)alkylthio; (4) CN; (5) haloalkyl, preferably CF₃; (6) lower alkyl; (7)N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl; (10) —C(R 2)(R¹³)—OD¹; (11) —C(R2)(R 3)—O-lower alkyl; (12) lower alkyl-CO₂D¹; (13) lower alkyl-CO₂R¹²;(14) benzyloxy; (15) —O-(lower alkyl)-CO₂D¹; (16) —O-(loweralkyl)-CO₂R¹²; or (17) —O-(lower alkyl)-NR¹²R¹³; (d) unsubstituted,mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is amonocyclic aromatic ring of 5 atoms, said ring having one heteroatomwhich is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; orsaid heteroaryl is a monocyclic ring of 6 atoms, said ring having oneheteroatom which is N, and, optionally 1, 2, or 3 additional N atoms,and wherein said substituents are each independently: (1) halo; (2)lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl,preferably CF₃; (7) N₃; (8) —C(R¹²)(R¹³)—OD¹; or (9)—C(R¹²)(R¹³)—O-lower alkyl; (e) unsubstituted, mono- or di-substitutedbenzoheterocycle, wherein the benzoheterocycle is a 5, 6, or 7-memberedring which contains 1 or 2 heteroatoms independently selected from O, S,or N, and, optionally, a carbonyl group or a sulfonyl group, whereinsaid substituents are each independently: (1) halo; (2) lower alkyl; (3)alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl, preferably CF₃; (7) N₃;(8) —C(R¹²)(R¹³)—OD¹; or (9) —C(R²)(R³)—O-lower alkyl; (f)unsubstituted, mono- or di-substituted benzocarbocycle, wherein thecarbocycle is a 5, 6, or 7-membered ring which optionally contains acarbonyl group, wherein said substituents are each independently: (1)halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl,preferably CF₃; (7) N₃; (8) —C(R¹²)(R¹³)—OD¹; or (9)—C(R¹²)(R¹³)—O-lower alkyl; (g) hydrogen; or (h) K R¹² and R¹³ are eachindependently: (a) hydrogen; (b) lower alkyl; or (c) aryl; or R¹² andR¹³ together with the atom to which they are attached form a saturatedmonocyclic ring of 3, 4, 5, 6 or 7 atoms; R¹⁴ and R are eachindependently: (a) hydrogen; or (b) lower alkyl; or R¹⁴ and R¹⁵ togetherwith the atom to which they are attached form a carbonyl, a thial, or asaturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; Q is: (a)—C(O)—U-D¹; (b) —CO₂-lower alkyl; (c) tetrazolyl-5-yl; (d)—C(R⁷)(R⁸)(S-D¹); (e) —C(R⁷)(R⁸)(O-D¹); or (f) —C(R⁷)(R⁸)(O-loweralkyl); X⁵ is: (a) —(CR³¹R³²)_(a)—; (b) —(CR³¹R³²)_(bb)-A¹-; (c) -A—(CR³¹R³²)_(bb)—; (d) —CR³¹R³²-A¹-CR³¹R³²; (e) —CR³¹═; or (f) -A¹; A¹is: (a) oxygen; (b) thio; (c) sulfinyl; (d) sulfonyl; or (c) —N(R³³)—;R³¹ and R³² are each independently: (a) hydrogen; (b) lower alkyl; (c)substituted lower alkyl; (d) lower alkoxy; (e) lower haloalkyl; or (f)halo; or R³¹ and R³² taken together are; (a) oxo; (b) thial; (c) oxime;or (d) hydrazone; R³³ is: (a) lower alkyl; (b) hydrogen; or (c) —C(O)H;a is an integer equal to 1 or 3; bb is an integer equal to 2 or 3; D¹is: (a) hydrogen or (b) D; D is: (a) V; or (b) K; U is: (a) oxygen; (b)sulfur; or (c) —N(R_(a))(R_(i))—; V is: (a) —NO; (b) —NO₂; or (c)hydrogen K is—W_(aa)-E_(b)-(C(R_(e))(R_(f)))_(p)-E_(c)—(C(R_(e))(R_(f)))_(n)-W_(d)-(C(R_(e))(R_(f)))_(y)-W_(i)-E_(j)-W_(g)-(C(R_(e))(R_(f)))_(z)—U—V;wherein aa, b, c, d, g, i and j are each independently an integer from 0to 3; p, x, y and z are each independently an integer from 0 to 10; W ateach occurrence is independently: (a) —C(O)—; (b) —C(S)—; (c) -T-; (d)—(C(R_(e))(R_(f)))_(h)—; (e) alkyl; (f) aryl; (g) heterocyclic ring; (h)arylheterocyclic ring, or (i) —(CH₂CH₂O)_(q)—; E at each occurrence isindependently a -T- group, an alkyl group, an aryl group, a heterocyclicring, —(C(R_(e))(R_(f)))_(h)—, an arylheterocyclic ring or—(CH₂CH₂O)_(q)—; h is an integer form 1 to 10; q is an integer from 1 to5; R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, analkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, anarylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, ahaloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, anarylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, anaminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, aalkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, acarbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl,an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, anitro, -T-Q′-, or —(C(R_(g))(R_(h)))_(k)-T-Q′ or R_(e) and R_(f) takentogether are an oxo, a thial, a heterocyclic ring, a cycloalkyl group,an oxime, a hydrazone or a bridged cycloalkyl group; Q′ is —NO or —NO₂;k is an integer from 1 to 3; T is independently a covalent bond, acarbonyl, an oxygen, —S(O)O— or —N(R_(a))R_(i)—, o is an integer from 0to 2, R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester,an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, analkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy,an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, anaminoalkyl, an aminoaryl, —OR′_(i), —CH₂—C(T-Q′)(R_(g))(R_(h)), a bondto an adjacent atom creating a double bond to that atom or —(N₂O₂—)⁻.M⁺,wherein M⁺is an organic or inorganic cation; with the proviso that whenR_(i) is —CH₂—C(T-Q′)(R_(g))(R_(h)) or —(N₂O₂—).M⁺; then “-T-Q′” can bea hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group; R_(g) and R_(h) at each occurrence areindependently R_(e); R′_(i) is independently selected from R_(i);wherein the compound of Formula (II) is:

wherein: A-B is: (a) N—C; (b) C—N; or (c) N—N; when A-B is N—C, sides dand f are double bonds, and sides e and g are single bonds, —X²-Y²-Z²-is: (a) ═CR⁴—CR⁴′═CR⁵—; (b) ═N—CR⁴═CR⁴—; (c) ═N—CR⁴═N—; (d) ═CR⁴—N═CR⁴′;(e) ═CR⁴—N═N—; (f) ═N—N═CR⁴—; (g) ═N—N═N—; or (h) ═CR⁴—CR⁵═N—; when A-Bis C—N, sides e and g are double bonds, and sides d and f are singlebonds, —X²-Y²-Z²- is: (a) —CR⁴═N—N═; (b) —N═N—CR⁴═; (c) —CR⁴═N—CR⁴′═;(d) —N═CR⁴—N═; (e) —CR⁴═CR⁴′-N═; (f) —N═CR⁴—CR⁵═; (g) —CR⁴═CR⁵—CR^(5′)═;or (h) —N═N—N═; when A-B is C—N, side g is a double bond, and sides d, eand f are single bonds, —X²—Y²-Z²- is: (a) —C(O)—O—CR⁴═; (b)—C(O)—NR³—CR⁴═; (c) —C(O)—S—CR⁴═; or (d) —C(H)R⁴—C(OH)R⁵—N═; when A-B isN—C, sides d is a double bond, and sides e, f and g are single bonds,—X²—Y²-Z²- is: (a) ═CR⁴—O—C(O)—; (b) ═CR⁴—NR³—C(O)—; (c) ═CR⁴—S—C(O)—;or (d) ═N—C(OH)R⁴—C(H)R⁵—; when sides f is a double bond, and sides d, eand g are single bonds, —X²—Y²-Z²- is: (a) —CH(R⁴)—CR⁵═N—; or (b)—C(O)—CR⁴═CR⁵—; when sides e is a double bond, and sides d, f and g aresingle bonds, —X²—Y²-Z²- is: (a) —N═CR⁴—CH(R⁵)—; or (b) —CR⁴═CR⁵—C(O)—;when sides d, e, f and g are single bonds, —X²—Y²-Z²- is: (a)—C(O)—CR⁴(R^(4′))—C(O)—; and with the proviso that when A-B is C—N, thenX⁵ must be —(CR³¹R³²)_(a) or —(CR³¹R³²)_(bb)-A¹; and wherein R¹, R^(1′),R², R³, R⁴, R⁴′, R⁵, R⁵′, X⁵ A¹, R³¹, R³², a and bb are as definedherein; wherein the compound of Formula (III) is:

wherein: X³ is: (a) —C(O)—U-D¹; (b) —CH₂—U-D¹; (c) —CH₂—C(O)—CH₃; (d)—CH₂—CH₂—C(O)—U-D¹; (e) —CH₂—O-D¹; (f) —C(O)H or (g) —C(O)-U-R¹²; Y³ is:(a) —(CR⁵(R⁵′))_(k)—U-D¹; (b) —CH₃; (c) —CH₂OC(O)R⁶; or (d) —C(O)H; R⁸²,R^(82′), R⁸³ and R^(83′) are each independently: (a) hydrogen; (b)hydroxy; (c) alkyl; (d) alkoxy; (e) lower alkyl-OD¹; (f) alkylthio; (g)CN; (h) —C(O)R⁸⁴; or (i) —OC(O)R⁸⁵; R⁸⁴ is: (a) hydrogen; (b) loweralkyl; or (c) alkoxy; R⁸⁵ is: (a) lower alkyl; (b) alkoxy (c)unsubstituted, mono-, di- or tri-substituted phenyl or pyridyl, whereinthe substituents are each independently: (1) halo; (2) alkoxy; (3)haloalkyl; (4) CN; (5) —C(O)R⁸⁴; (6) lower alkyl; (7) —S(O)₀-loweralkyl; or (8) —OD¹; alternatively, R⁸² and R⁸³ or R^(82′) and R^(83′)taken together are: (a) oxo; (b) thial; (c) ═CR⁸⁶R⁸⁷; or (d) ═NR⁸⁸; R⁸⁶and R⁸⁷ are each independently: (a) hydrogen; (b) lower alkyl; (c) loweralkyl-OD¹; (d) CN; or (e) —C(O)R⁸⁴; R⁸⁸ is: (a) OD¹; (b) alkoxy; (c)lower alkyl; or (d) unsubstituted, mono-, di- or tri-substituted phenylor pyridyl, wherein the substituents are each independently: (1) halo;(2) alkoxy; (3) haloalkyl; (4) CN; (5) —C(O)R⁸⁴; (6) lower alkyl; (7)—S(O)₀-lower alkyl; or (8) —OD¹; X⁶ is: (a) —(CR³¹R³²)_(a)—; (b)—(CR³¹R³²)_(bb)-A¹-; or (e) —CR³¹═; and wherein R¹, R^(1′), R², R⁵, R⁵′,R⁶, R¹², R³¹, R³², A¹, U, D¹, a, bb, o and k are as defined herein;wherein the compound of Formula (IV) is:

wherein: X⁴ and Z⁴ are each independently: (a) N; or (b) CR²¹; R²⁰ is:(a) —S(O)₂—CH₃; (b) —S(O)₂—NR⁸(D¹); or (c) —S(O)₂—N(D¹)-C(O)—CF₃; R²¹and R^(21′) are each independently: (a) hydrogen; (b) lower alkyl; (c)alkoxy; (d) alkylthio; (e) haloalkyl, preferably fluoroalkyl; (f)haloalkoxy, preferably fluoroalkoxy; (g) CN; (h) —CO₂D¹; (i) —CO₂R¹⁴;(j) lower alkyl-O-D¹; (k) lower alkyl-CO₂D¹; (l) lower alkyl-CO₂R¹⁴; (m)halo; (n) —O-D¹; (o) —N₃; (p) —NO₂; (q) —NR¹⁴D¹; (r) —N(D¹)C(O)R¹⁴; (s)—NHK; (t) aryl; (u) arylalkylthio; (v) arylalkoxy; (w) alkylamino; (x)aryloxy; (y) alkylarylalkylamino; (z) cycloalkylalkylamino; or (aa)cycloalkylalkoxy; R²² is: (a) mono-, di- or tri-substituted phenyl orpyridinyl (or the N-oxide thereof), wherein the substituent are eachindependently: (1) hydrogen; (2) halo; (3) alkoxy; (4) alkylthio; (5)CN; (6) lower alkyl; (7) haloalkyl, preferably fluoroalkyl; (8) N₃; (9)—CO₂D¹; (10) —CO₂-lower alkyl; (11) —C(R¹⁴)(R¹⁵)—OD¹; (12) —OD¹; (13)lower alkyl-CO₂—R¹⁴; or (14) lower alkyl-CO₂-D¹; (b)-T-C(R²³)(R²⁴)(C(R²⁵)(R²⁶))_(o)—C(R²⁷)(R²⁸)—U-D¹;

(d) arylalkyl; or (e) cycloalkylalkyl; wherein: R¹⁴ and R¹⁵ are eachindependently: (a) hydrogen; or (b) lower alkyl; R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸ are each independently: (a) hydrogen; or (b) lower alkyl; orR²³ and R²⁷, or R²⁷ and R²⁸ together with the atoms to which they areattached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R²³ andR²⁵ are joined to form a covalent bond; Y⁵ is: (a) CR²⁹R³⁰; (b) oxygen;or (c) sulfur; R²⁹ and R³⁰ are each independently: (a) hydrogen; (b)lower alkyl; (c) (CH₂)_(o)—OD¹; (d) halo; or R²⁹ and R³⁰ taken togetherare an oxo group; s is an integer from 2 to 4; and wherein R^(1′), R⁸,X⁵, D¹, T, U, K and o are as defined herein; wherein the compound ofFormula (V) is:

wherein: X⁷ is: (a) oxygen; (b) sulfur; (c) —NR⁵¹; (d) —N—O—R⁵²; or (e)—N—NR⁵²R⁵³; Y⁷ at each occurrence is independently: (a) hydrogen; (b)halo; (c) lower alkyl; (d) alkenyl; or (e) alkynyl; Z⁷ is: (a)—(CR³¹R³²)_(a)—; R⁴⁹ is: (a) R³; or (b) R⁴; R⁵⁰ and R^(50′) are eachindependently: (a) hydrogen; (b) halo; (c) lower alkyl; (d) aryl; (e)arylalkyl; (f) cycloalkyl; (g) cycloalkylalkyl; (h) —OD¹; (i) loweralkyl-OD¹; (j) carboxamido; (k) amidyl; or (l) K; R⁵¹ is: (a) loweralkyl; (b) alkenyl; (c) cycloalkyl; (d) cycloalkylalkyl; (e) aryl; (f)arylalkyl; (g) heterocyclic ring; or (h) lower alkyl-heterocyclic ring;R⁵² and R⁵³ are each independently: (a) lower alkyl; (b) cycloalkyl; (c)cycloalkylalkyl; (d) aryl; (e) arylalkyl; (f) heterocyclic ring; or (g)heterocyclicalkyl; and wherein R¹, R³, R⁴, R³¹, R³², K, D¹ and a are asdefined herein; wherein the compound of Formula (VI) is:

wherein: X⁹ is —C(O)-U-D¹ and Y⁹ is —CH₂—CR⁵(R⁵′)—U-D¹; or X⁹ is—CH₂—CR⁵(R^(5′))—U-D¹ and Y⁹ is —C(O)-U-D¹; or X⁹ and Y⁹ taken togetherare: (a) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—; (b)—(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—CR⁵(R^(5′))—; (c)—C(O)—(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—; (d)—(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—C(O)—; or (e)—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—; wherein X⁹ is the first carbon atom ofa, b, c, d and e; and wherein R¹, R^(1′), R², R⁴, R⁴′, R⁵, R⁵′, X⁶, U,D¹ and k are as defined herein; wherein the compound of Formula (VII)is:

wherein: when side h, k, and j are single bonds, and side i and l are adouble bond, —X¹⁰—Y¹⁰-Z¹⁰- is:

when sides i, k and l are single bonds, and sides h and j are doublebonds, —X¹⁰—Y¹⁰-Z¹⁰- is:

when side h and j are single bonds, l is a double bond, and side k and iis a single or a double bond, —X¹⁰—Y¹⁰-Z¹⁰- is:

P¹⁰ is: (a) —N═; (b) —NR³—; (c) —O—; or (d) —S—; Q¹⁰ and Q^(10′) areeach independently: (a) CR⁶⁰; or (b) nitrogen; A¹⁰-B¹⁰-C¹⁰-D¹⁰- is: (a)—CR⁴═CR^(4′)—CR⁵═CR^(5′)—; (b)—CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—C(O)—; (c)—CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—CR⁴(R^(4′))—; (d)—CR⁴(R^(4′))—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—; (e)—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—; (f)—CR⁴(R⁴)—CR⁵(R^(5′))—C(O)—; (g) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—; (h)—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—; (i) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—C(O)—;(j)-CR⁴(R^(4′))—O—C(O)—CR⁵(R^(5′))—; (k)—O—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—; (l) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—O—;(m) —CR⁴(R^(4′))—C(O)—O—CR⁵(R^(5′))—; (n)—C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—; (o) —CR¹²(R¹³)—O—C(O)—; (p)—C(O)—O—CR¹²(R¹³)—; (q) —O—C(O)—CR¹²(R¹³)—; (r) —CR¹²(R¹³)—C(O)—O—; (s)—N═CR⁴—CR^(4′)═CR⁵—; (t) —CR⁴═N—CR^(4′)═CR⁵—; (u) —CR⁴═CR^(4′)—N═CR⁵;(v) —CR⁴═CR⁵—CR^(5′)═N—; (w) —N═CR⁴—CR^(4′)═N—; (x) —N═CR⁴—N═CR^(4′)—;(y) —CR⁴═N—CR^(4′)═N—; (z) —S—CR⁴═N—; (aa) —S—N═CR⁴—; (bb) —N═N—NR³—(cc) —CR⁴═N—S—; (dd) —N═CR⁴—S—; (ee) —O—CR⁴═N—; (ff) —O—N═CR⁴—; or (gg)—N═CR⁴—O—; A¹⁰′-B¹⁰′-D¹⁰′ is: (a) —CR⁴═CR⁵—CR^(5′)═ (b)—CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—; (c)—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—; (d) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—; (e)—N═CR⁴—CR⁵═; (g) —N═N—CR⁴═; (h) —N═N—NR³—; (i) —N═N—N═; (j) —N═CR⁴—NR³—;(k) —N═CR⁴—N═; (l) —CR⁴═N—NR³—; (m) —CR⁴═N—N═; (n) —CR⁴═N—CR⁵═; (o)—CR⁴═CR⁵—NR³—; (p) —CR⁴═CR⁵—N═; (q) —S—CR⁴═CR⁵—; (r) —O—CR⁴═CR⁵; (s)—CR⁴═CR⁵—O—; (t) —CR⁴═CR⁵—S—; (u) —CR⁴═N—S—; (v) —CR⁴═N—O—; (w)—N═CR⁴—S—; (x) —N═CR⁴—O—; (y) —S—CR⁴═N—; (z) —O—CR⁴═N—; (aa) —N═N—S—;(bb) —N═N—O—; (cc) —S—N═N—; (dd) —O—N═N—; (ee) —CR⁴═CR⁵—S; (ff)—CR⁴(R^(4′))—CR⁵(R^(5′))—S—; (gg) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—; (hh)—S—CR⁴(R^(4′))—CR⁵(R^(5′))—; or (ii) —O—CR⁴(R^(4′))—CR⁵(R^(5′))—; R⁶⁰and R⁶¹ are each independently: (a) lower alkyl; (b) haloalkyl,preferably fluoroalkyl; (c) alkoxy; (d) alkylthio; (e) lower alkyl-OD¹;(f) —C(O)H; (h) —(CH₂)_(q)—CO₂-lower alkyl; (i) —(CH₂)_(q)—CO₂D¹; (j)—O—(CH₂)_(q)—S-lower alkyl; (k) —(CH₂)_(q)—S-lower alkyl; (l)—S(O)₂-lower alkyl; (m) —(CH₂)_(q)—NR¹²R¹³; or (n) —C(O)N(R⁸)(R⁸); andwherein R¹, R^(1′), R², R³, R⁴, R^(4′), R⁵, R^(5′), R⁸, R¹², R¹³, X⁵, T,D¹ and q are as defined herein; wherein the compound of Formula (VIII)is:

wherein: X¹⁴ is: (a) —C(O)—; or (b) —C(S)—; Y¹⁴ is: (a) —O—; or (b) —S—;A¹⁴-B¹⁴-D¹⁴- is: (a) —CR⁴═CR^(4′)—CR═CR^(5″)—; (b)—CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—; (c) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—; (d)—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—; (e) —CR⁴(R⁵)—O—C(O)—; (f)—C(O)—O—CR⁴(R⁵)—; (g) —O—C(O)—CR⁴(R⁵)—; (h) —S—N═CR⁴—; (i) —O—N═CR⁴—;(j) —CR⁴(R⁵)—NR³—C(O)—; (k) —C(O)—NR³—CR⁴(R)—; (l) —NR³—C(O)—CR⁴(R⁵)—;(m) —CR⁴(R⁵)—S—C(O)—; (n) —C(O)—S—CR⁴(R⁵)—; (o) —S—C(O)—CR⁴(R⁵)—; (p)—CR⁴═CR^(4′)—C(O)—; (q) —C(O)—CR⁴═CR^(4′)—; (r) —O—CR⁴═CR^(4′)—; (s)—S—CR⁴═CR^(4′)—; (t) —NR³—CR⁴═CR⁵—; (u) —S—NR³—C(O)—; (v) —O—NR³—C(O)—;or (w) —NR³—N═CR⁴—; and wherein R¹, R^(1′), R², R³, R⁴, R^(4′), R⁵,R^(5′) and X⁵ are as defined herein.
 2. A composition comprising thecompound of claim 1 and a pharmaceutically acceptable carrier.
 3. Amethod for treating or reducing inflammation, pain or fever in a patientin need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim
 2. 4. Amethod for treating a gastrointestinal disorder, or improving thegastrointestinal properties of a COX-2 inhibitor in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 2. 5. The method of claim4, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia6. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 2. 7. The method of claim 6, whereinthe wound is an ulcer.
 8. A method for treating or reversing renaland/or respiratory toxicity in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 2. 9. A method for treating a disorder resultingfrom elevated levels of COX-2 in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 2. 10. The method of claim 9, wherein the disorderresulting from elevated levels of COX-2 is angiogenesis, arthritis,asthma, bronchitis, menstrual cramps, premature labor, tendinitis,bursitis, a skin-related condition, neoplasia, an inflammatory processin a disease, an ophthalmic disorder, pulmonary inflammation, a centralnervous system disorder, allergic rhinitis, respiratory distresssyndrome, endotoxin shock syndrome, atherosclerosis, a microbialinfection, a cardiovascular disorder, a urinary disorder, a urologicaldisorder, endothelial dysfunction, organ deterioration, tissuedeterioration, or activation, adhesion and infiltration of neutrophilsat the site of inflammation.
 11. The method of claim 10, wherein theneoplasia is a brain cancer, a bone cancer, an epithelial cell-derivedneoplasia (epithelial carcinoma), a basal cell carcinoma, anadenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer,an esophageal cancer, a small bowel cancer, a stomach cancer, a coloncancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovarycancer, a cervical cancer, a lung cancer, a breast cancer, a skincancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, arenal cell carcinoma, a cancerous tumor, a growth, a polyp, anadenomatous polyp, a familial adenomatous polyposis or a fibrosisresulting from radiation therapy.
 12. The method of claim 10, whereinthe central nervous system disorder is cortical dementia, Alzheimer'sdisease, vascular dementia, multi-infarct dementia, pre-senile dementia,alcoholic dementia, senile dementia, or central nervous system damageresulting from stroke, ischemia or trauma.
 13. A method for inhibitingplatelet aggregation in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 2. 14. The composition of claim 2, furthercomprising at least one therapeutic agent.
 15. The composition of claim14, wherein the therapeutic agent is a steroid, a nonsteroidalantiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, aleukotriene B₄ receptor antagonist, a leukotriene A₄ hydrolaseinhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme Ainhibitor, a H₂ antagonist, an antineoplastic agent, an antiplateletagent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, adiuretic, a sedating or non-sedating anti-histamine, an inducible nitricoxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pyloriinhibitor, a proton pump inhibitor, an isoprostane inhibitor, or amixture of two or more thereof.
 16. The composition of claim 15, whereinthe nonsteroidal antiinflammatory compound is acetaminophen, aspirin,diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.
 17. Amethod for treating or reducing inflammation, pain or fever in a patientin need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim
 14. 18. Amethod for treating a gastrointestinal disorder, or improving thegastrointestinal properties of a COX-2 inhibitor in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 14. 19. The method of claim18, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia.20. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 21. The method of claim 20,wherein the wound is an ulcer.
 22. A method for treating or reversingrenal and/or respiratory toxicity in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 23. A method for treating adisorder resulting from elevated levels of COX-2 in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 14. 24. The method of claim23, wherein the disorder resulting from elevated levels of COX-2 isangiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis, a skin-related condition, neoplasia, aninflammatory process in a disease, an ophthalmic disorder, pulmonaryinflammation, a central nervous system disorder, allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, a microbial infection, a cardiovascular disorder, aurinary disorder, a urological disorder, endothelial dysfunction, organdeterioration, tissue deterioration, or activation, adhesion andinfiltration of neutrophils at the site of inflammation.
 25. The methodof claim 24, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 26. The method of claim 24,wherein the central nervous system disorder is cortical dementia,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, or centralnervous system damage resulting from stroke, ischemia or trauma.
 27. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 28. A composition comprising atleast one compound of claim 1 and at least one compound that donates,transfers or releases nitric oxide, or induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor, or is asubstrate for nitric oxide synthase.
 29. The composition of claim 28,further comprising a pharmaceutically acceptable carrier.
 30. Thecomposition of claim 28, wherein the compound that donates, transfers,or releases nitric oxide, or induces the production of endogenous nitricoxide or endothelium-derived relaxing factor or is a substrate fornitric oxide synthase is an S-nitrosothiol.
 31. The composition of claim30, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine,S-nitroso-captopril, S-nitroso-N-acetylpenicillamine,S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, orS-nitroso-cysteinyl-glycine.
 32. The composition of claim 30, whereinthe S-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(m)SNO; (ii)ONS(C(R_(e))(R_(f)))_(m)R_(e); or (iii)H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein m isan integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or—(C(R_(g))(R_(h)))_(k)-T-Q′ or R_(e) and R_(f) taken together are anoxo, a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, ahydrazone or a bridged cycloalkyl group; Q′ is —NO or —NO₂; and T isindependently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R¹ is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T-Q′)(R_(g))(R_(h)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T-Q′)(R_(g))(R_(h)) or —(N₂O₂—).M⁺; then “-T-Q′” can be ahydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group; and R_(g) and R_(h) at each occurrenceare independently R_(e).
 33. The composition of claim 28, wherein thecompound that donates, transfers, or releases nitric oxide, or inducesthe production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase isL-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylatedL-homoarginine), citrulline, ornithine, glutamine, lysine, an arginaseinhibitor or a nitric oxide mediator.
 34. The composition of claim 28,wherein the compound that donates, transfers, or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase is: (i) a compound that comprises at least one ON—O— or ON—N—group; (ii) a compound that comprises at least one O₂N—O—, O₂N—N— orO₂N—S— or group; (iii) a N-oxo-N-nitrosoamine having the formula:R^(1″)R^(2″)N—N(O-M⁺)—NO, wherein R^(1″) and R^(″) are eachindependently a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andM⁺ is an organic or inorganic cation.
 35. The composition of claim 34,wherein the compound comprising at least one ON—O— or ON—N— group is anON—O-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-aminoacid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, anON-N-oligonucleotide, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, astraight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic ON—N-hydrocarbon, anON—O-heterocyclic compound or an ON—N-heterocyclic compound.
 36. Thecomposition of claim 34, wherein compound comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group is an O₂N—O-polypeptide, anO₂N—N-polypeptide, an O₂N-S-polypeptide, an O₂N—O-amino acid,O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—O-sugar, an O₂N—N-sugar,O₂N—S-sugar, an O₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N-S-oligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted O₂N—O-hydrocarbon, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted O₂N—N-hydrocarbon, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted O₂N—S-hydrocarbon, an O₂N—O-heterocyclic compound, anO₂N—N-heterocyclic compound or an O₂N—S-heterocyclic compound.
 37. Thecomposition of claim 28, further comprising at least one therapeuticagent.
 38. The composition of claim 37, wherein the therapeutic agent isa steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase(5-LO) inhibitor, a leukotriene B₄ receptor antagonist, a leukotriene A4hydrolase inhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H₂antagonist, an antineoplastic agent, an antiplatelet agent, a thrombininhibitor, a thromboxane inhibitor, a decongestant, a diuretic, asedating or non-sedating anti-histamine, an inducible nitric oxidesynthase inhibitor, an opioid, an analgesic, a Helicobacter pyloriinhibitor, a proton pump inhibitor, an isoprostane inhibitor, or amixture of two or more thereof.
 39. The composition of claim 38, whereinthe nonsteroidal antiinflammatory compound is acetaminophen, aspirin,diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.
 40. Amethod for treating or reducing inflammation, pain or fever in a patientin need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim 29 or 37.41. A method for treating a gastrointestinal disorder, or improving thegastrointestinal properties of a COX-2 inhibitor in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim 29 or
 37. 42 The method ofclaim 41, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia.43. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 29 or
 37. 44. The method of claim 43,wherein the wound is an ulcer.
 45. A method for treating or reversingrenal and/or respiratory toxicity in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 29 or
 37. 46. A method for treating adisorder resulting from elevated levels of COX-2 in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim 29 or
 37. 47. The method ofclaim 46, wherein the disorder resulting from elevated levels of COX-2is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps,premature labor, tendinitis, bursitis, a skin-related condition,neoplasia, an inflammatory process in a disease, an ophthalmic disorder,pulmonary inflammation, a central nervous system disorder, allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, a microbial infection, a cardiovascular disorder, aurinary disorder, a urological disorder, endothelial dysfunction, organdeterioration, tissue deterioration, or activation, adhesion andinfiltration of neutrophils at the site of inflammation.
 48. The methodof claim 47, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 49. The method of claim 47,wherein the central nervous system disorder is cortical dementia,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, or centralnervous system damage resulting from stroke, ischemia or trauma.
 50. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 29 or
 37. 51. A kit comprising atleast one compound of claim
 1. 52. The kit of claim 51, furthercomprising (i) at least one compound that donates, transfers or releasesnitric oxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase; (ii) at least one therapeutic agent; or (iii) at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase and at least onetherapeutic agent.
 53. The kit of claim 52, wherein the at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase; the at least onetherapeutic agent; or the at least one compound that donates, transfersor releases nitric oxide, induces the production of endogenous nitricoxide or endothelium-derived relaxing factor, or is a substrate fornitric oxide synthase and at least one therapeutic agent; are in theform of separate components in the kit
 54. A kit comprising thecomposition of claim 14, 29 or
 37. 55. A compound selected from thegroup consisting of:1-(1-(cyclohexylmethyl)-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;4-(1-(cyclohexylmethyl)-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;1-(3-(hydroxymethyl)-1-benzylpyrazol-5-yl)-4-(methylsulfonyl)benzene;1-(3-((1E)-3-hydroxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;1-(1-(cyclohexylmethyl)-3-(3-hydroxypropyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;1-(1-(cyclohexylmethyl)-3-vinylpyrazol-5-yl)-4-(methylsulfonyl)benzene;methyl(2E)-3-(1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)prop-2-enoate; methyl5-(4-(methylsulfonyl)phenyl)-1-benzylpyrazole-3-carboxylate;1-(1-(cyclohexylmethyl)-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;4-(1-(cyclohexylmethyl)-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;4-(methylsulfonyl)-1-(3-((nitrooxyl)methyl)-1-benzylpyrazol-5-yl)benzene;1-(3-((1E)-3-nitrooxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;1-(1-(cyclohexylmethyl)-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl)phenyl ketone;2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrile;3-fluorophenyl 2-(4-methylsulfonylphenyl)(3-pyridyl) ketone2-(4-(methylsulfonyl)phenyl)(3-pyridyl) 2-pyridyl ketone; ethyl3-((2-(4-(methylsulfonyl)phenyl)-3-pyridyl)carbonyl)benzoate; or apharmaceutically acceptable salt thereof.
 56. A composition comprisingat least one compound of claim 55 and a pharmaceutically acceptablecarrier.
 57. The composition of claim 56, further comprising (i) atleast one compound that donates, transfers or releases nitric oxide,induces the production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase; (ii) atleast one therapeutic agent; or (iii) at least one compound thatdonates, transfers or releases nitric oxide, induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor, or is asubstrate for nitric oxide synthase and at least one therapeutic agent.58. A kit comprising at least one compound of claim 55.